Apelin receptor agonists and methods of use

ABSTRACT

The present invention provides compounds of Formula (I): wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are APJ agonists which may be used as medicaments.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to priority pursuant to 35 U.S.C. § 119(e)to U.S. provisional patent application No. 62/263,106, filed Dec. 4,2015, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention provides substituted hydroxypyrimidinones, andtheir analogues thereof, which are APJ agonists, compositions containingthem, and methods of using them, for example, for the treatment orprophylaxis of heart failure, atherosclerosis, ischemic heart diseaseand related conditions.

BACKGROUND OF THE INVENTION

Heart failure (HF) and related complications constitute major healthburden in developed countries with an estimated prevalence of 5,700,000in the United States alone (Roger, V. L. et al., Circulation,125(1):e2-e220 (2012)). Despite considerable advances in recent twodecades, the prognosis remains very poor, with survival rates of only˜50% within 5-years of diagnosis (Roger, V. L. et al., JAMA,292(3):344-350 (2004)). In addition to poor survival, the impairedquality of life and recurrent hospitalizations constitute clear unmetmedical need for development of novel treatment options.

HF is a clinical syndrome characterized by the inability of the heart todeliver sufficient supply of blood and oxygen to meet the metabolicdemands of organs in the body. Main symptoms associated with HF includeshortness of breath due to pulmonary edema, fatigue, reduced toleranceto exercise and lower extremity edemas. The etiology of HF is highlycomplex with multiple associated risk factors and potential causes.

Among the leading causes of HF are coronary artery disease and cardiacischemia, acute myocardial infarction, intrinsic cardiomyopathies andchronic uncontrolled hypertension. HF can develop either acutely(functional impairment post myocardial infarction) or as a chroniccondition, characterized by long-term maladaptive cardiac tissueremodeling, hypertrophy and cardiac dysfunction (for example due touncontrolled long-term hypertension). According to the diagnosticcriteria and type of ventricular dysfunction, HF is classified to twomajor groups, HF with “reduced ejection fraction” (HFrEF) or HF with“preserved ejection fraction” (HFpEF). Both types are associated withsimilar signs and symptoms, but differ in the type of ventricularfunctional impairment (Borlaug, B. A. et al., Eur. Heart J.,32(6):670-679 (2011)).

APJ receptor (APLNR) and its endogenous peptidic ligand apelin have beenimplicated as important modulators of cardiovascular function andcandidates for therapeutic intervention in HF (for review see Japp, A.G. et al., Biochem. Pharmacol., 75(10):1882-1892 (2008)).

Accumulated evidence from preclinical disease models and human heartfailure patients have implicated apelin and APJ agonism as beneficial inthe setting of HF. Mice lacking Apelin or APJ gene have impaired myocytecontractility (Charo, D. N. et al., Am. J. Physiol. Heart Circ.Physiol., 297(5):H1904-H1913 (2009)). Apelin knockout (KO) mice developprogressive cardiac dysfunction with aging and are more susceptible toHF in the model of trans-aortic constriction (TAC) (Kuba, K. et al.,Circ. Res., 101(4):e32-42 (2007)). The functional impairment in chronicHF is a result of prolonged demand on the heart and is associated withmaladaptive cardiac remodeling, manifested by the cardiac hypertrophy,increased inflammation and interstitial fibrosis which eventually leadto decrease in cardiac performance.

Acute administration of apelin increases cardiac output in rodents undernormal conditions and also in models of heart failure (Berry, M. F.,Circulation, 110(11 Suppl. 1):II187-II193 (2004)). Increased cardiacoutput is a result of direct augmentation of cardiac contractility andreduced peripheral vascular resistance in the arterial and venous beds(Ashley, E. A., Cardiovasc. Res., 65(1):73-82 (2005)). Reduction in thevascular resistance leads to lower pre-load and after-load on the heartand thus lesser work load (Cheng, X. et al., Eur. J. Pharmacol.,470(3):171-175 (2003)). Similar to rodent studies, acute infusion ofapelin to healthy human subjects and patients with heart failureproduces similar hemodynamic responses with increased cardiac output andincreased vasodilatory response in peripheral and coronary arteries(Japp, A. G. et al., Circulation, 121(16):1818-1827 (2010)).

The mechanisms underlying inotropic action of apelin are not wellunderstood, but appear to be distinct from clinically used PI-adrenergicagonists (dobutamine) due to lack of increase in heart rate. Thevasodilatory action of apelin is primarily mediated via endothelialnitric oxide synthase pathways (Tatemoto, K., Regul. Pept.,99(2-3):87-92 (2001)). Apelin is induced under hypoxic conditions,promotes angiogenesis and has been shown to limit the infarct size inischemia-reperfusion models (Simpkin, J. C., Basic Res. Cardiol.,102(6):518-528 (2007)).

In addition to aforementioned studies evaluating acute administration ofapelin, several studies have clearly demonstrated beneficial effects ofprolonged administration of apelin in a number of chronic rodent modelsof HF, including the angiotensin II model, TAC model and rat Dahlsalt-sensitive model (Siddiquee, K. et al., J. Hypertens., 29(4):724-731(2011); Scimia, M. C. et al., Nature. 488(7411):394-398 (2012); Koguchi,W. et al., Circ. J. 76(1):137-144 (2012)). In these studies, prolongedapelin infusion reduced cardiac hypertrophy and cardiac fibrosis, andwas associated with improvement in cardiac performance.

Genetic evidence is also emerging that polymorphisms in the APJ gene areassociated with slower progression of HF (Sarzani, R. et al., J. Card.Fail. 13(7):521-529 (2007)). Importantly, while expression of APJ andapelin can be reduced or vary considerably with HF progression, thecardiovascular hemodynamic effects of apelin are sustained in patientswith developed HF and receiving standard of care therapy (Japp, A. G. etal., Circulation, 121(16):1818-1827 (2010)).

In summary, there is a significant amount of evidence to indicate thatAPJ receptor agonism plays a cardioprotective role in HF and would be ofpotential benefit to HF patients. Apelin's very short half life incirculation limits its therapeutic utility, and consequently, there is aneed for APJ receptor agonists with improved pharmacokinetic andsignaling profile while maintaining or enhancing the beneficial effectsof endogenous APJ agonist apelin.

SUMMARY OF THE INVENTION

The present invention provides substituted hydroxypyrimidinones, andtheir analogues thereof, which are useful as APJ agonists, includingstereoisomers, tautomers, pharmaceutically acceptable salts, or solvatesthereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ, suchas heart failure, coronary artery disease, cardiomyopathy, diabetes andrelated conditions including but not limited to acute coronary syndrome,myocardial ischemia, hypertension, pulmonary hypertension, coronaryvasospasm, cerebral vasospasm, ischemia/reperfusion injury, angina,renal disease, metabolic syndrome and insulin resistance.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomerand, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, wherein:

-   alk is C₁₋₆ alkyl substituted with 1-5 R⁴;-   ring A is independently selected from 5- or 6-membered aryl and    heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from    N, NR^(3a), O, and S, each substituted with 1-4 R³;-   ring B is independently selected from aryl, heteroaryl, and    cycloalkyl, each substituted with 1-4 R¹;-   R¹ is independently selected from H, halogen, NO₂, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₁₋₅ alkenyl substituted with 0-3 R^(e), aryl substituted    with 1-3 R^(e), heterocyclyl substituted with 0-3 R^(e), and C₃₋₆    cycloalkyl substituted with 0-3 R^(e); provided when R² is C₁₋₅    alkyl, the carbon atom and the groups attached thereto except the    one attached to the pyrimidine ring may be replaced by O, N, and S;-   R³ is independently selected from H, halogen, —(CH₂)_(n)OR^(b),    —(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₅ alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(3a) is independently selected from H, —S(O)_(p)R_(c),    —C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)OR^(b), —S(O)_(p)NR^(a)R^(a),    C₁₋₅ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R⁴ is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),    C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and    heterocyclyl;-   R^(d), at each occurrence, is independently selected from H and C₁₋₆    alkyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),    NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),    NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f), at each occurrence, is independently selected from H, F, Cl,    Br, CN, OH, C₁₋₅alkyl (optionally substituted with halogen and OH),    C₃₋₆ cycloalkyl, and phenyl, or R^(f) and R^(f) together with the    nitrogen atom to which they are both attached form a heterocyclic    ring optionally substituted with C₁₋₄alkyl;-   n is independently selected from zero, 1, 2, and 3; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In a second aspect, the present disclosure provides a compound ofFormula (I), or a stereoisomer, an enantiomer, a diastereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof,within the scope of any of the first aspect, wherein:

-   ring A is independently selected from

-   ring B is independently selected from

and 6-membered heteroaryl, each substituted with 1-4 R¹;

-   R¹ is independently selected from H, F, Cl, Br, NO₂,    —(CH₂)_(n)OR^(b), —(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e) and    C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 1-3 R¹, heterocyclyl    substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² is    C₁₋₅ alkyl, the carbon atom and the groups attached thereto except    the one attached to the pyrimidine ring may be replaced by O, N, and    S;-   R³ is independently selected from H, halogen, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)R^(b),    —(CH₂)_(n)NHC(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)OR^(b), —(CH₂)_(n)O    C(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NHS(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NHS(O)_(p)R^(c), C₁₋₅ alkyl substituted with 0-3 R^(e),    (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),    NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f),    NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f), at each occurrence, is independently selected from H, F, Cl,    Br, CN, OH, C₁₋₅alkyl (optionally substituted with halogen and OH),    C₃₋₆ cycloalkyl, and phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In a third aspect, the present disclosure provides a compound of Formula(II):

-   -   or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer,        a pharmaceutically acceptable salt, or a solvate thereof, within        the scope of the first or second aspect, wherein:

-   ring A is independently selected from

-   R¹ is independently selected from F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 1-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl and —(CH₂)₁₋₄OC₁₋₅alkyl,    and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ is independently selected from H, F, Cl, Br, —OR^(b),    —(CH₂)_(n)C(═O)R^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NHC(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, CH₃, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(a), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and    CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a fourth aspect, the present disclosure provides a compound ofFormula (III):

-   -   or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer,        a pharmaceutically acceptable salt, or a solvate thereof, within        the scope of any of the first, second and third aspects,        wherein:

-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl and    CH₂O(CH₂)₁₋₃CH₃;

-   R³ is independently selected from H, F, Cl, Br, —OC₁₋₄alkyl,    S(O)₂C₁₋₄alkyl R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), —C(═O)NR^(a)R^(a), —NHC(═O)R^(b), C₁₋₄ alkyl    substituted with 0-3 R^(e), and heterocyclyl selected from

-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e); R^(e), at each occurrence, is independently selected    from C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃,    OCF₃, —(CH₂)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and    CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a fifth aspect, the present disclosure provides a compound of Formula(III), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer,a pharmaceutically acceptable salt, or a solvate thereof, within thescope of any of the first, second, third, and fourth aspects, wherein:

-   R³ is independently selected from H and —(CH₂)₀₋₁NR^(a)R^(a)a;-   R^(a) and R^(a) together with the nitrogen atom to which they are    both attached form a heterocyclic ring selected from

-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and    CO₂H.

In a sixth aspect, the present disclosures provides a compound ofFormula (III), or a stereoisomer, an enantiomer, a diastereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof,within the scope of any of the first, second and third aspects, wherein:

-   ring A is independently selected from

-   R¹ is independently selected from F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, and    CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from H, C₁₋₄ alkyl substituted with 0-3    R^(e), and phenyl substituted with 0-3 R¹;-   R^(3a) is independently selected from H, CH₃, and —(CH₂)_(n)-phenyl    substituted with 0-3 R^(e); and-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and CO₂H.

In a seventh aspect, the present disclosures provides a compound ofFormula (IV):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, within the scopeof the first aspect, wherein:

-   -   ring A is independently selected from

-   -   ring B is independently selected from

-   R¹ is independently selected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, and    C₁₋₄ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl and    CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from H, F, Cl, Br, —OR^(b),    —(CH₂)_(n)C(═O)R^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NHC(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, CH₃, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    and CH₂OCH₃;-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀    carbocyclyl substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl    substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In an eighth aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the eighth aspect.

In another aspect, the present invention provides compounds of Formula(Ia):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   alk is C₁₋₆ alkyl substituted with 1-5 R⁴;-   ring A is independently selected from 5- or 6-membered aryl and    heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from    N, NR^(3a), O, and S, each substituted with 1-4 R³;-   ring B is independently selected from aryl, heteroaryl, and    cycloalkyl, each substituted with 1-4 R¹;-   R¹ is independently selected from H, halogen, NO₂, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n) OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(e),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), aryl substituted    with 0-3 R^(e), heterocyclyl substituted with 0-3 R^(e), and C₃₋₆    cycloalkyl substituted with 1-3 R^(e); provided when R² is C₁₋₅    alkyl, the carbon atom and the groups attached thereto except the    one attached to the pyrimidine ring may be replaced by O, N, and S;-   R³ is independently selected from H, halogen, —(CH₂)OR^(b),    —(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₅ alkyl substituted with 0-3 R^(e), (CH₂)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl comprising    carbon atoms and 1-4 heteroatoms selected from N, NR³¹, O, S, and    substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, —S(O)_(p)R_(c),    —C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)OR^(b), —S(O)_(p)NR^(a)R^(a),    C₁₋₅ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R⁴ is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e), (CH₂)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),    C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and    heterocyclyl;-   R^(d), at each occurrence, is independently selected from H and C₁₋₆    alkyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with halogen, OH, and CN), C₂₋₆ alkenyl,    C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,    NO₂, ═O, CO₂H, —(CH₂)OR^(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),    NR^(f)C(═O)R^(f), S(O),NR^(f)R^(f), NR^(a)S(O)_(p)R^(f),    NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)NR^(f)R^(f);-   R^(f), at each occurrence, is independently selected from H,    C₁₋₅alkyl (optionally substituted with halogen and OH), C₃₋₆    cycloalkyl, and phenyl, or R^(f) and R^(f) together with the    nitrogen atom to which they are both attached form a heterocyclic    ring optionally substituted with C₁₋₄alkyl;-   n is independently selected from zero, 1, 2, and 3; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In another aspect, the present invention provides compounds of Formula(Ia), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   ring A is independently selected from

-   ring B is independently selected from

and 6-membered heteroaryl, each substituted with 1-4 R¹;

-   R¹ is independently selected from H, F, Cl, Br, NO₂,    —(CH₂)_(n)OR^(b), —(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(e), —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e)    and C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 1-3 R^(e), heterocyclyl    substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² is    C₁₋₅ alkyl, the carbon atom and the groups attached thereto except    the one attached to the pyrimidine ring may be replaced by O, N, and    S;-   R³ is independently selected from H, halogen, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)R_(c),    —(CH₂)_(n)NHC(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)OR^(b), —(CH₂)O    C(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NHS(O),NR^(a)R^(a),    —(CH₂)_(n)NHS(O)R^(e), C₁₋₅ alkyl substituted with 0-3 R^(e),    (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl comprising carbon atoms and 1-4 heteroatoms    selected from N, NR^(3a), O, S, and substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀    carbocyclyl substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl    substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with halogen, OH, and CN), C₂₋₆ alkenyl,    C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,    NO₂, ═O, CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f),    NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f), NR^(a)S(O)_(p)R^(f),    NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and —(CH₂)NR^(f)R^(f),-   R^(f), at each occurrence, is independently selected from H,    C₁₋₅alkyl (optionally substituted with halogen and OH), C₃₋₆    cycloalkyl, and phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   ring A is independently selected from

-   R¹ is independently selected from F, Cl, OH, C₁₋₃ alkyl, and OC₁₋₃    alkyl;-   R^(1a) is independently selected from F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 1-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl and —(CH₂)₁₋₄OC₁₋₅alkyl,    and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ is independently selected from H, F, Cl, Br, —OR^(b),    —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)S(O)_(p)R_(c),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,    —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂),NHC(═O)R^(b), C₁₋₄ alkyl    substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl comprising carbon atoms    and 1-4 heteroatoms selected from N, NR^(3a), O, S, and substituted    with 0-3 R^(e);-   R^(3a) is independently selected from H, CH₃, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, and CONH₂; and-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(III):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   R¹ is independently selected from C₁₋₃ alkyl and —OC₁₋₃ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 1-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl,    and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ is independently selected from H, F, Cl, Br, —OC₁₋₄alkyl,    S(O)₂C₁₋₄alkyl R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), —C(═O)NR^(a)R^(a), —NHC(═O)R^(b), C₁₋₄ alkyl    substituted with 0-3 R^(e), C₃₋₆ carbocyclyl selected from

and heterocycyl selected from

-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and    CO₂H, and CONH₂; and-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(IIIa):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   R¹ is independently selected from C₁₋₃ alkyl and —OC₁₋₃ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e), phenyl substituted with 1-3 R^(e), 5-membered heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl,    and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R^(3b) is independently selected from H, F, Cl, and Br;-   R^(3c) is independently selected from H, —(CH₂)_(n)NR^(a)R^(a),

-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)—C₃₋₆    cycloalkyl, —(CH₂)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(IIIa), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   R¹ is independently selected from C₁₋₃ alkyl and —OC₁₋₃ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 5-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl and    CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from H and —(CH₂)₀₋₁NR^(a)R^(a);-   R^(a) and R^(a) together with the nitrogen atom to which they are    both attached form a heterocyclic ring selected from

-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and    CO₂H.

In another aspect, the present invention provides compounds of Formula(lIa), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   ring A is independently selected from

-   R¹ is independently selected from F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 5- or    6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl    and CH₂(CH₂)₁₋₃CH₃;-   R³ is independently selected from H, C₁₋₄ alkyl substituted with 0-3    R^(e), and phenyl substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, CH₃, and —(CH₂)-phenyl    substituted with 0-3 R^(e); and-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and    CO₂H;    and other variables are as defined in Formula (IIIa).

In another aspect, the present invention provides compounds of Formula(IV):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   ring A is independently selected from

-   -   ring B is independently selected from

-   R¹ is independently selected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, and    C₁₋₄ alkyl;-   R² is independently selected from C₂₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 5- or    6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl    and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from H, F, Cl, Br, —OR^(b),    —(CH₂)_(n)C(═O)R^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NHC(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    (CH₂)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(3a) is independently selected from H, CH₃, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    and CH₂OCH₃;-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)—C₃₋₁₀ carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, and CONH₂; and-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(V):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein:

-   R¹ is independently selected from H, F, Cl, Br, OC alkyl, CN, and    C₁₋₄ alkyl;-   R² is independently selected from —CH₂(CH₂)₁₋₃CH₃, —CH₂OCH(CH₃)₂,    —CH₂)₁₋₃C₃₋₆cycloalkyl,

5-membered heteroaryl selected from

and CH₂O(CH₂)₁₋₃CH₃;

-   R³ is independently selected from H, F, Cl, Br, C₃₋₆alkyl, phenyl    substituted with 0-3 R^(e), and 5- or 6-membered heteroaryl    substituted with 0-3 R^(e);-   R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    and CH₂OCH₃;-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃ cycloalkyl, —(CH₂)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(VI):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   R¹ is independently selected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, and    C₁₋₄ alkyl;-   R² is independently selected from —CH₂(CH₂)₁₋₃CH₃, —CH₂OCH(CH₃)₂,    —(CH₂)₁₋₃C₃₋₆cycloalkyl,

5-membered heteroaryl selected from

and CH₂O(CH₂)₁₋₃CH₃;

-   R^(3b) is independently selected from H and F;-   R^(3c) is independently selected from

-   R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    and CH₂OCH₃;-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, and CONH₂; and-   n is independently selected from zero, 1, 2, and 3.

In one non-limiting embodiment of Formula (IIIa), ring A is

ring B is

R¹ is independently selected from Et and OMe; R² is independentlyselected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂OCH(CH₃)₂, —CH₂OC₃₋₆cycloalkyl, —CH₂CH₂C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl,

R^(3b) is independently selected from H, F, Cl, and Br; R^(3c) isindependently selected from H, —OC₁₋₄alkyl, NH₂C(═O)C₁₋₄alkyl,—C(═O)NHC₁₋₄alkyl, —S(O)₂C₁₋₃ alkyl, —S(O)₂NH₂, C₁₋₄ alkyl substitutedwith 0-3 R^(e),

R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl(optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and n isindependently selected from zero, 1, 2, and 3.

In another non-limiting embodiment of Formula (IIIa), ring A is

ring B is

R¹ is independently selected from Et and OMe; R² is independentlyselected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂OCH(CH₃)₂, —CH₂OC₃₋₆cycloalkyl, —CH₂CH₂C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl

R^(3b) is independently selected from H, F, Cl, and Br; R^(3c) is—(CH₂)₀₋₁NR^(a)R^(a) wherein R^(a) and R^(a) together with the nitrogenatom to which the are both attached form a heterocyclic ring selectedfrom

R^(e), at each occurrence, is independently selected from C₁₋₃ alkyl, F,Cl, and Br.

In another non-limiting embodiment of Formula (IIIa), ring A is

ring B is

R¹ is independently selected from Et and OMe; R² is independentlyselected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂OCH(CH₃)₂, —CH₂OC₃₋₆cycloalkyl, —CH₂CH₂C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl,

R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl(optionally substituted with F and Cl), OH, OCH₃, OCF₃, F, Cl, Br, andCN.

In another non-limiting embodiment of Formula (IIIa), ring A isindependently selected from

ring B is

R¹ is independently selected from Et and OMe; R² is independentlyselected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂OCH(CH₃)₂, —CH₂OC₃₋₆cycloalkyl, —CH₂CH₂C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl,

R³ and R^(3a) are independently selected from H, C₁₋₄ alkyl, and

R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl(optionally substituted with F and Cl), OH, OCH₃, OCF₃, F, Cl, Br, andCN.

In one non-limiting embodiment of Formula (VI), ring A is

ring B

R¹ is independently selected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, andC₁₋₄ alkyl; R² is independently selected from —CH₂CH₂CH₂CH₃,—CH₂CH₂CH(CH₃)₂, —CH₂OCH(CH₃)₂, —CH₂OC₃₋₆ cycloalkyl, —CH₂CH₂C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl,

R^(3b) is independently selected from H, F, Cl, and Br, R^(3c) isindependently selected from H, —OC₁₋₄alkyl, NH₂C(═O)C₁₋₄alkyl,—C(═O)NHC₁₋₄alkyl, —S(O)₂C₁₋₃ alkyl, —S(O)₂NH₂, C₁₋₆ alkyl substitutedwith 0-3 R^(e),

R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, andCH₂OCH₃; R^(e), at each occurrence, is independently selected from C₁₋₆alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,—(CH₂)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and n isindependently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides a compound selectedfrom

-   3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (1),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(4-methoxyphenyl)methyl]-3,4-dihydropyrimidin-4-one    (2),-   2-butyl-6-hydroxy-3-(2-methoxyphenyl)-5-[(4-methoxyphenyl)methyl]-3,4-dihydropyrimidin-4-one    (3),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(1,2,4-oxadiazol-3-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (4),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (5),-   2-butyl-3-(2,6-dimethoxyphenyl)-5-{[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl}-6-hydroxy-3,4-dihydropyrimidin-4-one    (6),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(4-methanesulfonylphenyl)methyl]-3,4-dihydropyrimidin-4-one    (7),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(5-methyl-1,2-oxazol-3-yl)methyl]-3,4-dihydropyrimidin-4-one    (8),-   N-(4-({[2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}phenyl)acetamide    (9),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (10),-   2-butyl-5-{[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (11),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (12),-   2-butyl-3-(2,6-dimethoxyphenyl)-5-{[3-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl}-6-hydroxy-3,4-dihydropyrimidin-4-one    (13),-   2-butyl-5-{[6-(4-chlorophenyl)pyridin-3-yl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (14),-   4-{[2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-N-ethylbenzamide    (15),-   N-(4-{[1-(2,6-dimethoxyphenyl)-4-hydroxy-2-(3-methylbutyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}phenyl)acetamide    (16),-   3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-5-{[4-(1,2,4-oxadiazol-3-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (17),-   5-{[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-3,4-dihydropyrimidin-4-one    (18),-   5-benzyl-2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (19),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl)methyl}-3,4-dihydropyrimidin-4-one    (20),-   3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-5-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-3,4-dihydropyrimidin-4-one    (21),-   2-butyl-5-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (22),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[2-(4-methylphenyl)-1,3-thiazol-4-yl]methyl}-3,4-dihydropyrimidin-4-one    (23),-   2-butyl-5-{[1-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (24),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[1-(4-methylphenyl)-1H-pyrazol-4-yl]methyl}-3,4-dihydropyrimidin-4-one    (25),-   2-butyl-5-{[2-(4-chlorophenyl)-1,3-thiazol-5-yl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (26),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(1H-pyrazol-1-ylmethyl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (27),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (28),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[6-(4-methoxyphenyl)pyridin-3-yl]methyl}-3,4-dihydropyrimidin-4-one    (29),-   5-[(1-benzyl-1H-pyrazol-4-yl)methyl]-2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (30),-   5-{[1-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl}-3-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (31),-   3-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-{[4-(1,2,4-oxadiazol-3-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (32),-   5-{[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}-3-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (33),-   3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (34),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-({[4-(2-oxopiperidin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (35),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(morpholin-4-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (36),-   3-(2,6-dimethoxyphenyl)-5-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)benzyl)-2-(4-fluorophenyl)-6-hydroxypyrimidin-4(3H)-one    (37),-   2-cyclopentyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (38),-   2-(cyclobutoxymethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (39),-   2-(cyclopropoxymethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (40),-   2-(2-cyclopropylethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (41),-   2-butyl-5-{[4-(4-chloro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (42),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(4-methyl-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (43),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(6-methylpyridin-3-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (44),-   5-(([1,1′-biphenyl]-4-yl)methyl)-2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (45),-   2-butyl-5-{[4-(5-chloropyridin-2-yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (46),-   2-butyl-3-(2,6-dimethoxyphenyl)-5-{[4-(5-fluoro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-6-hydroxy-3,4-dihydropyrimidin-4-one    (47),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-methoxypyridin-3-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (48),-   2-butyl-5-{[4-(5-chloro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (49),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(5-methyl-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (50),-   2-cyclopentyl-3-(2,6-dimethoxyphenyl)-5-{[4-(5-fluoro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-6-hydroxy-3,4-dihydropyrimidin-4-one    (51),-   3-(2,6-dimethoxyphenyl)-5-{[4-(5-fluoro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-6-hydroxy-2-(3-methylbutyl)-3,4-dihydropyrimidin-4-one    (52),-   5-{[4-(5-chloro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-3,4-dihydropyrimidin-4-one    (53),-   3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(5-methyl-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-2-(3-methylbutyl)-3,4-dihydropyrimidin-4-one    (54),-   2-(2-cyclopropylethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(5-methyl-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one    (55),-   2-(2-cyclopropylethyl)-3-(2,6-dimethoxyphenyl)-5-{[4-(5-fluoro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-6-hydroxy-3,4-dihydropyrimidin-4-one    (56),-   5-{[4-(5-chloro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-2-(2-cyclopropylethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (57),-   3-(2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(5-methyl-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-2-[(propan-2-yloxy)methyl]-3,4-dihydropyrimidin-4-one    (58),-   3-(2,6-dimethoxyphenyl)-5-{[4-(5-fluoro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-6-hydroxy-2-[(propan-2-yloxy)methyl]-3,4-dihydropyrimidin-4-one    (59),-   5-{[4-(5-chloro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-3,4-dihydropyrimidin-4-one    (60),-   2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-(3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)benzyl)-6-hydroxypyrimidin-4(1H)-one    (61),-   1-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (62),-   1-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (63),-   2-butyl-1-(2,6-diethylphenyl)-5-{[4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (64),-   2-butyl-1-(2,6-diethylphenyl)-5-{[4-(6-fluoropyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (65),-   2-butyl-1-(2,6-diethylphenyl)-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (66),-   2-butyl-5-[(4-cyclopropylphenyl)methyl]-1-(2,6-diethylphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (67),-   5-({[1,1′-biphenyl]-4-yl)methyl}-2-butyl-1-(2,6-diethylphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (68),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (69),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (70),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (71),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (72),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (73),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (74),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (75),-   1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[3-fluoro-4-(3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (76),-   1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (77),-   1-(2,6-diethylphenyl)-5-{([3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (78),-   1-(2,6-diethylphenyl)-5-({[3-fluoro-4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (79),-   1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[3-fluoro-4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (80),-   4′-({[1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-4-oxo-1,4-dihydropyrimidin-5-yl]methyl}-2′,5-difluoro-[1,1′-biphenyl]-2-carboxamide    (81),-   4′-{[1-(2,6-diethylphenyl)-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-4-oxo-1,4-dihydropyrimidin-5-yl]methyl}-2′,4-difluoro-[1,1′-biphenyl]-2-carboxamide    (82),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl]methyl}-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-on    (83),-   4′-({[1-(2,6-diethylphenyl)-6-hydroxy-4-oxo-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-5-yl]methyl}-2′,4-difluoro-[1,1′-biphenyl]-2-carboxamide    (84),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (85),-   1-(2,6-diethylphenyl)-5-{[2-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (86),-   1-(2,6-diethylphenyl)-5-({[3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl]methyl}-6-hydroxy-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (87),-   1-(2,6-diethylphenyl)-5-{[2-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl]methyl}-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (88),-   4′-{[1-(2,6-diethylphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-4-oxo-1,4-dihydropyrimidin-5-yl]methyl}-3′,4-difluoro-[1,1′-biphenyl]-2-carboxamide    (89),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl]methyl}-6-hydroxy-2-[1-(2-methylpropyl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (90),-   1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-[1-(2-methylpropyl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (91),-   4′-{[1-(2,6-diethylphenyl)-6-hydroxy-2-[1-(2-methylpropyl)-H-pyrazol-3-yl]-4-oxo-1,4-dihydropyrimidin-5-yl]methyl}-2′,4-difluoro-[1,1′-biphenyl]-2-carboxamide    (92),-   2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-{[3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (93),-   4′-{[2-(I-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidin-5-yl]methyl}-2′,4-difluoro-[1,1′-biphenyl]-2-carboxamide    (94),-   (S)-3-(1-(2-butyl-5-(4-(6-fluoro-2-methylpyridin-3-yl)benzyl)-6-hydroxy-4-oxopyrimidin-1(4H)-yl)propyl)benzonitrile    (95),-   3-[(1S)-1-(2-butyl-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-4-oxo-1,4-dihydropyrimidin-1-yl)propyl]benzonitrile    (96),-   3-[(1S)-1-(2-butyl-5-{[4-(6-fluoropyridin-3-yl)phenyl]methyl}-6-hydroxy-4-oxo-1,4-dihydropyrimidin-1-yl)propyl]benzonitrile    (97),-   3-[(1S)-1-(2-butyl-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-4-oxo-1,4-dihydropyrimidin-1-yl)propyl]benzonitrile    (98),-   3-[(1S)-1-(2-butyl-5-({[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-4-oxo-1,4-dihydropyrimidin-1-yl)propyl]benzonitrile    (99),-   3-[(1S)-1-(2-butyl-5-({[4-(5-chloro-2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-6-hydroxy-4-oxo-1,4-dihydropyrimidin-1-yl)propyl]benzonitrile    (100),-   3-[(1S)-1-{2-butyl-5-[(4-cyclopropylphenyl)methyl]-6-hydroxy-4-oxo-1,4-dihydropyrimidin-1-yl}propyl]benzonitrile    (101),-   3-[(1S)-1-{2-butyl-5-[(4-cyclopropylphenyl)methyl]-6-hydroxy-4-oxo-1,4-dihydropyrimidin-1-yl}propyl]benzonitrile    (102),-   2-butyl-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-1-[(1S)-1-(3-fluorophenyl)propyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (103),-   2-butyl-5-{[4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-1-[(1S)-1-(3-fluorophenyl)propyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (104),-   2-butyl-1-[(1S)-1-(3-fluorophenyl)propyl]-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (105),-   2-butyl-1-[(1S)-1-(3-fluorophenyl)propyl]-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (106),-   2-(2-cyclopropylethyl)-1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-({[4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (107),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (108),-   2-(2-cyclopropylethyl)-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (109),-   2-(2-cyclopropylethyl)-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (110),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (111),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-{[4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (112),-   2-(2-cyclopropylethyl)-1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (113),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (114),-   1-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (115),-   4′-({1-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]-6-hydroxy-4-oxo-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-5-yl)methyl}-4-fluoro-[1,1′-biphenyl]-2-carboxamide    (116),-   4′-{[2-(2-cyclopropylethyl)-1-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]-6-hydroxy-4-oxo-1,4-dihydropyrimidin-5-yl]methyl}-4-fluoro-[1,1′-biphenyl]-2-carboxamide    (117),-   5-{[3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-4-one    (118),-   5-{[3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl]methyl}-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-4-one    (119),-   2′,4-difluoro-4′-{[6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-4-oxo-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-5-yl]methyl}-[1,1′-biphenyl]-2-carboxamide    (120),-   3-fluoro-5-[(1S)-1-(6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-4-oxo-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-1-yl)-2-methylpropyl]benzonitrile    (121),-   1-[(1R)-1-(3,5-difluorophenyl)-2-methoxyethyl]-2-(ethoxymethyl)-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (122),-   1-[(1R)-1-(3,5-difluorophenyl)-2-methoxyethyl]-2-(ethoxymethyl)-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (123),-   1-[(1R)-1-(3,5-difluorophenyl)-2-methoxyethyl]-2-(ethoxymethyl)-5-{[4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (124),-   1-[(1R)-1-(3,5-difluorophenyl)-2-methoxyethyl]-2-(ethoxymethyl)-5-{[4-(6-fluoropyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (125),-   1-[(1R)-1-(3,5-difluorophenyl)-2-methoxyethyl]-2-(ethoxymethyl)-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (126),-   2-butyl-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-{[3-(3-methylpyridin-4-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (127),-   2-butyl-1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-{[3-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (128),-   2-butyl-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-{[3-(2-methylpyridin-3-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (129),-   2-butyl-1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-{[3-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (130),-   3′-({2-butyl-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-4-oxo-1,4-dihydropyrimidin-5-yl)methyl}-4-fluoro-[1,1′-biphenyl]-2-carboxamide    (131),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[4-(2-fluoro-3-methylpyridin-4-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (132),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-{[4-(2-methylpyridin-3-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (133),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[4-(6-fluoro-2-methylpyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (134),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-{[4-(6-fluoropyridin-3-yl)phenyl]methyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (135), and-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-{[4-(3-methylpyridin-4-yl)phenyl]methyl}-1,4-dihydropyrimidin-4-one    (136).

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements (including individual variable definitions) ofan embodiment are meant to be combined with any and all other elementsfrom any of the embodiments to describe additional embodiments. Thepresent invention also provides a pharmaceutical composition comprisinga compound of formula I, or an enantiomer, diastereomer, or apharmaceutically-acceptable salt, and a pharmaceutically acceptablecarrier therefore.

In another embodiment, the compounds of the present invention have EC₅₀values ≤10 μM, using the APJ hcAMP assay disclosed herein, preferably,EC₅₀ values ≤5 μM, more preferably, EC₅₀ values ≤1 μM, even morepreferably, EC₅₀ values ≤0.5 M, even more preferably, EC₅₀ values ≤0.1μM, even more preferably, EC₅₀ values ≤0.01 μM.

In another aspect, the present invention provides compounds selectedfrom any subset list of compounds exemplified in the presentapplication.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is A.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is B.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is C.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

The present invention provides a pharmaceutical composition furthercomprising additional therapeutic agent(s). In a preferred embodiment,the present invention provides pharmaceutical composition, wherein theadditional therapeutic agent is, for example, angiotensin convertingenzyme (ACE) inhibitor, β-adrenergic receptor blocker, angiotensin IIreceptor blocker, diuretic, aldosterone antagonist and digitaliscompound.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ or apelin activity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

Examples of diseases or disorders associated with the activity of theAPJ and apelin that can be prevented, modulated, or treated according tothe present invention include, but are not limited to heart failure suchas acute decompensated heart failure (ADHF), atrial fibrillation,coronary artery disease, peripheral vascular disease, atherosclerosis,diabetes, metabolic syndrome, hypertension, pulmonary hypertension,cerebrovascular disorders and the sequelae thereof, cardiovasculardisorders, angina, ischemia, stroke, myocardial infarction, acutecoronary syndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes and obesity.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure, coronary artery disease,peripheral vascular disease, atherosclerosis, diabetes, metabolicsyndrome, hypertension, pulmonary hypertension, atrial fibrillation,angina, ischemia, stroke, myocardial infarction, acute coronarysyndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes, obesity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure such as ADHF, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of diabetes and obesity, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of hypertension, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of pulmonary hypertension, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of acute coronary syndrome and cardiacischemia, comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention, alone, or,optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ andapelin.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of multiple diseases or disordersassociated with AP and apelin.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin, comprising administering to a patient inneed thereof a therapeutically effective amount of a first and secondtherapeutic agent, wherein the first therapeutic agent is a compound ofthe present invention. Preferably, the second therapeutic agent, forexample selected inotropic agent such as β-adrenergic agonist (forexample dobutamine).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

Where desired, the compound of the present invention may be used incombination with one or more other types of cardiovascular agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of cardiovascular agents that may beoptionally employed in combination with the APJ agonist of the presentinvention may be one, two, three or more cardiovascular agentsadministered orally in the same dosage form, in a separate oral dosageform, or by injection to produce an additional pharmacological benefit.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents:anti-hypertensive agents, ACE inhibitors, mineralocorticoid receptorantagonists, angiotensin receptor blockers, calcium channel blockers,β-adrenergic receptor blockers, diuretics, vasorelaxation agents such asnitrates, anti-atherosclerotic agents, anti-dyslipidemic agents,anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemicagents, anti-thrombotic agents, anti-retinopathic agents,anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents,calcium channel blockers, anti-obesity agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, agents for treatingheart failure, agents for treating peripheral arterial disease, agentsfor treating malignant tumors, and anti-inflammatory agents.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating heart failure: ACE inhibitors,β-blockers, diuretics, mineralocorticoid receptor antagonists, renininhibitors, calcium channel blockers, angiotensin II receptorantagonists, nitrates, digitalis compounds, inotropic agents.

The present invention may be embodied in other specific forms withoutparting from the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also understoodthat each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to C₁₈alkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and C₁₈ alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S- and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc.,New York (2007). “C₆₋₁₀ aryl” refers to phenyl and naphthyl. The term“benzyl”, as used herein, refers to a methyl group on which one of thehydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N-+O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, 4th Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, Jr., L. V.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   -   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and        Widder, K. et al., eds., Methods in Enzymology, 112:309-396,        Academic Press (1985);    -   b) Bundgaard, H., Chapter 5, “Design and Application of        Prodrugs”, Krosgaard-Larsen, P. et al., eds., A Textbook of Drug        Design and Development, pp. 113-191, Harwood Academic Publishers        (1991);    -   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);    -   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);    -   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and    -   f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and        Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl(e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C.G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tic” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “a”, “0”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

-   AcOH or HOAc acetic acid-   ACN Acetonitrile-   Alk Alkyl-   BBr₃ boron tribromide-   Bn benzyl-   Boc tert-butyloxycarbonyl-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   BuOH n-butanol-   t-BuOH tert-butanol-   Cbz carbobenzyloxy-   CDCl₃ deutero-chloroform-   CD₃OD deutero-methanol-   CH₂Cl₂ Dichloromethane-   CH₃CN Acetonitrile-   CHCl₃ Chloroform-   DCM Dichloromethane-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   Et Ethyl-   Et₃N or TEA triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   HCl hydrochloric acid-   HOAt 1-Hydroxy-7-azabenzotriazole-   HOBt 1-Hydroxybenzotriazole-   HPLC high-performance liquid chromatography-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium hydrogenphosphate-   LCMS liquid chromatography mass spectrometry-   LiHMDS lithium bis(trimethylsilyl)amide-   LG leaving group-   Me methyl-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OAc ammonium acetate-   Pd(OAc)₂ palladium(II) acetate-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(O)-   PG protecting group-   Ph phenyl-   Pr Propyl-   i-Pr isopropyl-   i-PrOH or IPA Isopropanol-   PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium-   hexafluorophosphate-   Rt retention time-   SiO₂ silica oxide-   SFC supercritical fluid chromatography-   TBAI tetrabutylammonium iodide-   TEA triethylamine-   FFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   TiCl₄ titanium tetrachloride-   T3P 1-propanephosphonic acid cyclic anhydride

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. et al., Protecting Groups inOrganic Synthesis, 4th Edition, Wiley (2007)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); Smith, M. B. et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure. 6th Edition, Wiley &Sons, New York, N.Y. (2007); Katritzky, A. R. et al, eds., ComprehensiveOrganic Functional Groups Transformations II, 2nd Edition, ElsevierScience Inc., Tarrytown, N.Y. (2004); Larock, R. C., ComprehensiveOrganic Transformations, VCH Publishers, Inc., New York, N.Y. (1999),and references therein.

Cyano containing intermediate compound 1c is either commerciallyavailable or readily synthesized by those skilled in the art. One ofsuch preparation from a corresponding commercially available carboxylicacid 1a is illustrated in Scheme 1. Formation of amides of generalformula 1b from acid 1a is readily performed by those skilled in theart. One of such example is by reacting acid 1a and ammonium chloridewith a base and a coupling agent under an inert environment. Preferredcoupling agents include HOAt, HOBt, BOP, PyBOP and preferred basesinclude TEA, Hunig's base and pyridine. Preferred solvents are DCM, THF,dioxane, ether, DMF and N-Methyl-2-pyrrolidone. Alternatively,carboxylic acid 1a can react with oxalyl chloride or thionyl chloride toform an acid chloride intermediate, which then reacts with ammonia toprovide amides of formula 1b. For conversion of amide 1b to cyano 1c, avariety of dehydrating agents such as TFAA, POCl₃ can be used. Preferredsolvents are ethers and chlorinated solvents.

The construction of target compounds of formula 2d is generallydescribed in scheme 2. Amine containing compounds of formula 2a arewidely available from commercial sources. Step 1 describes the formationof intermediate amidine of formula 2b by reacting cyano of formula 1c(Scheme 1) and amines of formula of 2a typically mediated by a Lewisacid under an inert environment at ambient to elevated temperature.Preferred Lewis acids include trimethylsilyl triflate, aluminum andtitanium based reagents, and preferred solvents are ethers, chlorinatedand hydrocarbon solvents such as dioxane, THF, dichloroethane andtoluene. Temperature can vary from ambient to 120° C. depending onR₂/ring B.

Step 2 describes the formation of hydroxypyrimidinone of formula 2c fromreacting amidine of formula 2b with a malonate derivative such asdiethyl malonate. Base is usually required for this transformation andpreferred bases are NaH, hexamethyldisilazide-, tert-butoxide-,ethoxide- and methoxide-based bases. Preferred solvents are ethers,chlorinated or alcoholic solvents and temperature can vary from ambientto 200° C. depending on R₂/ring B.

Step 3 describes the formation of target substituted hydroxypyrimidinoneof formula 2d by reacting 2c with an alkyl halide of general formula 1e.Alkyl halides are widely available from commercial sources and can bereadily prepared by those skilled in the art. The formation ofhydroxypyrimidinone 2d usually requires basic conditions and preferredbases are amine bases, carbonate bases, NaH, hexamethyldisilazide basedbases, and phosphazene bases. O-alkylated products can also be formedunder these reaction conditions. Preferred solvents used for thistransformation are DMF, acetone, ether, chlorinated, alcoholic oraqueous solvents and temperature can vary from ambient to 160° C.depending on R₂/ring B.

An alternative method to construct the dihydroxypyrimidine core ofinterest 2d is shown in Scheme 3 and Scheme 4. Scheme 3 describes thegeneration of alkylated malonic acid of formula 3b.

Alkyl halides of formula 1e are widely available from commercial sourcesand can be readily prepared by those skilled in the art. Alkylation ofdiethyl malonate with 1e under basic conditions leads to intermediatecompounds of formula 3a. This can be performed by first deprotonatingdiethyl malonate with an appropriate base such as NaH,hexamethyldisilazide, alkyl lithiums, carbonate bases, phosphazene basesin an inert solvent such as THF, DMF, chlorinated and ethereal solventsat temperatures varying from −78° C. to 100° C. depending on solvents,bases, and ring A.

Step 2 describes hydrolysis of ester 3a to the corresponding diacid offormula 3b. This transformation is typically conducted under basic oracidic conditions and has been extensively described in the literature.Preferred reagents include hydroxide, carbonate, hydride bases and acidssuch as HCl, H₂SO₄. Preferred solvents include aqueous and alcoholsolvents, most general organic solvents and temperatures can vary from0° C. to 100° C. depending on solvents, acids/bases, and ring A.

Scheme 4 describes an alternate method for the formation ofdihydroxypyrimidines of formula 2d. Diacids of formula 3b are firstconverted to the corresponding diacid chloride. Preferred reagents forthis transformation include oxalyl chloride, Ghosez reagent (Org. Synth.1979, 59, 26), and preferred solvents are chlorinated, ethereal, andhydrocarbon solvents such as ether, dichloromethane, and hexane.Temperature can vary from 0° C. to 60° C. depending on ring A. When theacid chloride formation is completed, in the same reaction vessel, baseand amidines of formula 2b can be added to allow the formation ofdihydroxypyrimidines 2d. Preferred bases are non protic bases such asHunig's base, phosphazenes, and temperature for this step can vary from0° C. to 60° C.

IV. Biology

APJ receptor was discovered in 1993 as an orphan G protein-coupledreceptor (GPCR) and was subsequently found to recognize apelin peptideas its endogenous ligand. It belongs to class A of GPCRs and has aclassical 7-transmembrane domain structure, exhibiting greatest sequencehomology to angiotensin AT1 receptor (for review see Pitkin, S. L. etal., Pharmacol. Rev., 62(3):331-342 (2010)). APJ is expressed in widevariety of peripheral tissues and the CNS, and has relatively highexpression in placenta, myocardium, vascular endothelial cells, smoothmuscle cells as well as cardiac myocytes (Kleinz, J. M. et al.,Pharmacol. Ther., 107(2):198-211(2005)). Apelin peptide was originallyidentified in bovine stomach extract and remains to date the only knownendogenous ligand and agonist of APJ receptor (Tatemoto, K. et al.,Biochem. Biophys. Res. Commun., 255:471-476 (1998)). Tissue expressionof apelin gene mirrors closely the APJ expression pattern and has beenpostulated to act in an autocrine or paracrine manner, often exemplifiedby reference to “apelin-APJ system”. Apelin gene encodes 77 amino acidprecursor peptide that is cleaved to form mature secreted peptideundergoing further proteolytic cleavage forming shorter C-terminalfragments. Apelin-36, -17 and -13 represent the major active forms withthe pyroglutamated form of apelin-13 being the most stable and the mostabundant form present in the cardiac tissue (Maguire, J. J. et al.,Hypertension, 54(3):598-604 (2009)). Apelin has very short half life incirculation, estimated to be less than 5 minutes (Japp, A. G. et al.,Circulation, 121(16):1818-1827 (2010)).

Activation of APJ receptor is known to inhibit forskolin-stimulatedcyclic AMP (cAMP) levels in pertussis toxin-sensitive manner, indicatingcoupling to the Gi proteins. The binding affinity of apelin and the EC₅₀values in the cAMP assay are reported to be in the sub-nanomolar range(for review see Pitkin, S. L. et al., Pharmacol. Rev.,62(3):331-342(2010)). In addition to cAMP inhibition, APJ receptoractivation also leads to β-arrestin recruitment, receptorinternalization and activation of extracellular-regulated kinases(ERKs)(for review see Kleinz, J. M. et al., Pharmacol. Ther.,107(2):198-211 (2005)). Which of these signaling mechanisms contributeto modulation of downstream physiological effects of apelin is not clearat present. APJ receptor has been shown to interact with the AT1receptor. While apelin does not bind AT1 and angiotensin II does notbind APJ, it has been postulated that certain physiological actions ofapelin are mediated, at least in part, via functional antagonism of theangiotensin II and AT1 receptor pathway (Chun, A. J. et al., J. Clin.Invest., 118(10):3343-3354 (2008)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known HF treatment agents, inone or more of the following categories that are given as examples, andare not intended to be limiting: (a) pharmacokinetic properties,including oral bioavailability, half life, and clearance; (b)pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor,(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with an APJagonist. Exemplary subjects include human beings of any age with riskfactors for development of heart failure and the sequelae thereof,angina, ischemia, cardiac ischemia, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia, stroke, as well as atherosclerosis,coronary artery disease, acute coronary syndrome, and/or dyslipidemias.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to modulate APJ and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

Assay Methods

Intracellular cAMP Accumulation Assay

HEK293 cells stably expressing human APJ receptor were used to assessthe activity of compounds. Cultured cells were detached and resuspendedin the cAMP Homogeneous Time-Resolved Fluorescence (HTRF) assay buffer(Cisbio cat; #62AM4PEJ). The assay was performed in 384-well assayplates (Perkin-Elmer; cat #6008289) according to assay protocol providedby the manufacturer. Serial dilutions of a compound together with assaybuffer containing 0.2 nM IBMX and 2 M forskolin were added to each wellcontaining 5,000 cells and incubated for 30 minutes at room temperature.Subsequently, cAMP D2 reagent was added in the lysis buffer followed bythe EuK antibody (Cisbio; cat #62AM4PEJ) and incubated for 60 min. Thefluorescence emission ratio was measured using fluorometer. Theintracellular cAMP concentrations (compound-stimulated inhibition offorskolin-mediated cAMP production) were calculated by extrapolationfrom a standard curve using known cAMP concentrations. The EC₅₀ valueswere obtained by fitting the data to a sigmoidal concentration-responsecurve with variable slope. The maximal achievable inhibition offorskolin-induced cAMP levels (Y_(max)) for each compound was expressedas relative percentage of inhibition attained using pyroglutamatedapelin-13 ((Pyr1)apelin-13) peptide, which was set to 100%.

The examples disclosed below were tested in the APJ in vitro assaysdescribed above and were found having human APJ cyclic AMP (hcAMP)activity. The EC₅₀ value of each compound is presented at the end of theexample description.

The compounds of the present invention possess activity as agonists ofAPJ receptor, and, therefore, may be used in the treatment of diseasesassociated with AP activity. Accordingly, the compounds of the presentinvention can be administered to mammals, preferably humans, for thetreatment of a variety of conditions and disorders, including, but notlimited to, treating, preventing, or slowing the progression of heartfailure, coronary artery disease, peripheral vascular disease,atherosclerosis, diabetes, metabolic syndrome and the sequelae ofthereof, hypertension, pulmonary hypertension, cerebrovasculardisorders, atrial fibrillation, angina, ischemia, stroke, myocardialinfarction, acute coronary syndrome, reperfusion injury, angioplasticrestenosis, vascular complications of diabetes and obesity.

The biological activity of the exemplified compounds of this inventiondetermined by the assay described above is shown at the end of eachexample. The APJ cAMP EC₅₀ potency ranges are as follows: A=0.01-10 nM;B=10.01-100 nM; C=100.01-300 nM.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, Jr., L. V. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012),

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., agents used intreatment of heart failure or other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other APJ agonists or one or more other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders including:agents for treating heart failure, anti-hypertensive agents,anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-thrombotic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-ischemic agents, anti-obesityagents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, memoryenhancing agents, anti-dementia agents, cognition promoting agents,appetite suppressants, and agents for treating peripheral arterialdisease.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingheart failure and coronary artery disease: ACE inhibitors, β-blockers,diuretics, mineralocorticoid receptor antagonists, renin inhibitors,calcium channel blockers, angiotensin II receptor antagonists, nitrates,digitalis compounds, inotropic agents and β-receptor agonists,anti-hyperlipidemic agents, plasma HDL-raising agents,anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors), LXR agonist, probucol,raloxifene, nicotinic acid, niacinamide, cholesterol absorptioninhibitors, bile acid sequestrants (such as anion exchange resins, orquaternary amines (e.g., cholestyramine or colestipol), low densitylipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate,cipofibrate, gemfibrizol, vitamin B₆, vitamin B12, anti-oxidantvitamins, anti-diabetes agents, platelet aggregation inhibitors,fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-diabetic agentsdepending on the desired target therapy. Studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Examples of anti-diabeticagents include, but are not limited to, sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide), biguanides (such asmetformin), thiazolidinediones (such as ciglitazone, pioglitazone,troglitazone, and rosiglitazone), and related insulin sensitizers, suchas selective and non-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); anti-glucocorticoids; TNFα inhibitors;dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin,saxagliptin), GLP-1 agonists or analogs (such as exenatide),α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretagogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the therapeutic agents discussed abovefor treating heart failure and atherosclerosis.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-obesity agentsselected from phenylpropanolamine, phentermine, diethylpropion,mazindol, fenfluramine, dexfenfluramine, phentiramine, β₃-adrenergicreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors(such as orlistat), and leptins. Other agents used in treating obesityor obesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D2receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients but also to control the release of one of these componentsin the gastrointestinal tract such that one of these components is notreleased in the stomach but rather is released in the intestines. One ofthe active ingredients may also be coated with a material that affects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the APJ receptor and apelin activity. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving APJ and apelin or anti-heart failureactivity. For example, a compound of the present invention could be usedas a reference in an assay to compare its known activity to a compoundwith an unknown activity. This would ensure the experimenter that theassay was being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving APJ and apelin.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof,and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ and apelin (as defined previously). Inanother embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with APJ and apelin. Thearticle of manufacture can further comprise: (d) a second container,wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

VI. Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As a person of ordinary skill in the art would be able to understandthat a hydroxypyrimidinone in a molecule may tautomerize to twodifferent enol forms as shown in the following equation, wherein R1, R2and R3 are as defined above, this disclosure is intended to cover allpossible tautomers even when a structure depicts only one of them.

Description of analytical LCMS methods:

Method A: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 ACN:water with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN:water with 10 mM NH₄OAc; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B;Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 mparticles; Mobile Phase A: 5:95 ACN:water with 0.1% TFA; Mobile Phase B:95:5 ACN:water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% Bover 3 minutes, then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min;Detection: UV at 220 nm.

Method C: Column: PHENOMENEX® Luna 3 μm C18 (2.0×30 mm); Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Gradient: 0-100% B over 2 minutes, then a 1 minute hold at100% B; Flow: 1 mL/min; Detection: UV at 220 nm.

Method D: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles;Mobile Phase A: water with 0.1% TFA; Mobile Phase B: ACN with 0.1% TFA;Gradient: 2-98% B over 1 minute, then a 0.5 minute hold at 98% B; Flow:0.8 mL/min; Detection: UV at 220 nm.

Method E: A linear gradient using solvent A (10% MeOH, 90% water, 0.1%TFA) and solvent B (90% MeOH, 10% water, 0.1% TFA); 0-100% of solvent Bover 4 min and then 100% of solvent B over 1 min. Column: PHENOMENEX®Luna 3 μm C18 (2.0×50 mm). Flow rate was 0.8 mL/min.

Example 13-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one

Compound 1a. 2-ethoxyacetamide

To a stirred solution of 2-ethoxyacetic acid (1.5 g, 14 mmol) in DCM (20mL) at 0° C. was added oxalyl chloride (8.7 mL, 17 mmol), followed byDMF (2 drops). The reaction was allowed to reach RT and stirred for 3hrs. The reaction mixture was concentrated under reduced pressure anddissolved in DCM (20 mL). Ammonia (20.6 mL, 144 mmol) (7 M in MeOH) wasadded slowly and the reaction mixture stirred for 16 hrs. The reactionmixture was concentrated under reduced pressure, dissolved in DCM,filtered and the solid further washed with DCM. The filtrate wasconcentrated to give Compound 1a (1 g, 9.7 mmol, 67% yield) as a whitesolid. 1H NMR (500 MHz, CDCl₃) δ 6.51 (br s, 1H), 5.46 (br s, 1H), 3.94(s, 2H), 3.59 (q, J=6.8 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).

Compound 1b. 2-ethoxyacetonitrile

To a stirred solution of Compound 1a (1.0 g, 9.7 mmol) in THF (10 mL) at0° C. was added pyridine (1.6 mL, 19 mmol) followed by TFAA (6.9 mL, 49mmol). The reaction was stirred for 1 hr. Aqueous NaHCO₃ solution wasadded carefully to the reaction mixture until the pH=8. The reactionmixture was extracted with DCM (2×). The organic layers were separated,combined and further washed with 1N HCl. The organic layer was driedover MgSO₄, filtered and concentrated in vacuo to give Compound 1b (0.80g, 9.4 mmol, 97% yield) as a yellow liquid. 1H NMR (500 MHz, CDCl₃) δ4.24 (s, 2H), 3.66 (q, J=6.9 Hz, 2H), 1.27 (t, J=6.9 Hz, 3H).

Compound 1c. N-(2,6-dimethoxyphenyl)-2-ethoxyacetimidamide

Trimethylaluminum (4.7 mL, 9.4 mmol) was added dropwise to a solution of2,6-dimethoxyaniline (1.2 g, 7.8 mmol) and Compound 1b (0.80 g, 9.4mmol) in toluene (10 mL) while cooling in an ice bath. After additionwas complete, the reaction mixture was warmed to 110° C. and was stirredat this temperature for 14 hrs. The cooled reaction mixture waspartitioned between a saturated solution of Rochelle's salt and EtOAc.The organic phase was separated, dried over MgSO₄, filtered andconcentrated under reduced pressure. The resulting residue was added toa silica gel (120 g) column and was eluted with 0-20% of 20% MeOH/DCM in0.5% TEA/DCM to give Compound 1c (1.1 g, 4.5 mmol, 57%) as a brownliquid. MS m/z=239.0 (M+H). 1H NMR (500 MHz, CDCl₃) δ 7.01 (t, J=8.3 Hz,1H), 6.62 (d, J=7.7 Hz, 2H), 5.32 (s, 2H), 4.88 (br s, 2H), 4.31 (s,2H), 3.82 (s, 6H), 3.62-3.73 (m, 2H), 1.19-1.33 (m, 3H).

Compound 1d.1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one

To a solution of Compound 1c (300 mg, 1.3 mmol) and diethyl malonate(1.0 mL, 6.3 mmol) in BuOH (5 mL) was added NaH (252 mg, 6.30 mmol)portionwise. Evolution of gas was observed. After evolution of gasceased, the reaction mixture was stirred at 110° C. for 2 hrs then 130°C. for 6 hrs. The reaction mixture was allowed to cool to RT and theresidue concentrated under reduced pressure to reduce the volume ofBuOH. The resulting residue was dissolved in water and DCM. The organiclayer was separated, dried over MgSO₄, filtered and concentrated invacuo. The residue was added to a silica gel (40 g) column and waseluted with 0-20% MeOH in DCM to give Compound 1d (100 mg, 0.30 mmol,26% yield) as a light brown liquid. MS m/z=239.0 (M+H). 1H NMR (500 MHz,CD₃OD) δ 7.47 (t, J=8.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 2H), 5.52 (s, 1H),4.05 (s, 2H), 3.81 (s, 6H), 3.39 (q, J=6.9 Hz, 2H), 1.08 (t, J=6.9 Hz,3H).

Compound 1e. 1-(4-(chloromethyl)phenyl)pyridin-2(1H)-one

To a stirred solution of 1-(4-(hydroxymethyl)phenyl)pyridin-2(1H)-one(150 mg, 0.7 mmol) in CHCl₃ (5 mL) was added thionyl chloride (0.16 mL,2.2 mmol). The reaction mixture was heated to 78° C. for 2 hrs. Thereaction mixture was allowed to cool and concentrated in vacuo. Theresidue was added to a silica gel (24 g) column and was eluted with20-100% EtOAc in hexanes, then 0-20% MeOH in DCM to give Compound 1e(150 mg, 0.70 mmol, 92% yield) as a white solid. MS m/z=222.0 (M+H). 1HNMR (500 MHz, CDCl₃) δ 7.52 (d, J=8.5 Hz, 2H), 7.38-7.42 (m, 3H), 7.32(dd, J=2.8, 6.3 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 6.24 (t, J=8.0 Hz, 1H),4.63 (s, 2H).

Example 1.3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylbutyl)-5-{[4-(2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one

To a suspension of Compound 1d (13 mg, 0.040 mmol) and Compound 1e (11.2mg, 0.0500 mmol) in acetone (1 mL) and water (0.1 mL) was added lithiumcarbonate (6.3 mg, 0.090 mmol) and TBAI (7.8 mg, 0.02 mmol). Thereaction mixture was heated at 50° C. for 20 hrs. The reaction mixturewas filtered and concentrated under reduced pressure. The residue waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile: water with 10 mM ammonium acetate; Gradient: 10-55% B over25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 1 (6.4 mg, 31% yield) as a white solid. Theestimated purity by LCMS analysis was 95%, HPLC method A, Rt=1.27 min,MS m/z=490.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ 7.63 (d, J=6.7 Hz, 1H),7.48-7.51 (m, 1H), 7.41 (t, J=8.5 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.25(d, J=8.2 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.47 (d, J=9.2 Hz, 1H), 6.29(t, J=5.8 Hz, 1H), 3.90 (s, 2H), 3.75 (s, 6H), 3.66 (s, 2H), 3.26 (q,J=7.0 Hz, 2H), 0.97 (t, J=7.0 Hz, 3H). Human APJ cAMP EC₅₀ potencyrange: C. Example 1′. An O-alkylated product Example 1′ (5.0 mg, 24%)was also isolated form the same reaction as a white solid. The estimatedpurity by LCMS analysis was 95%, HPLC method A, Rt=1.55 min, MSm/z=490.1 (M+H). The regiochemistry was determined by 2D NMR analysis.1H NMR (500 MHz, DMSO-d6) δ 7.68 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz,2H), 7.54 (dt, J=1.8, 7.0 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.46 (t,J=8.6 Hz, 1H), 6.84 (d, J=8.5 Hz, 2H), 6.50 (d, J=9.2 Hz, 1H), 6.34 (t,J=7.3 Hz, 1H), 5.76 (s, 1H), 5.36 (s, 2H), 3.98 (s, 2H), 3.76 (s, 6H),3.33 (q, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H).

Examples 2 to 36 were prepared as described in the general proceduregiven for Example 1.

APJ Rt(min) cAMP method Potency Ex# Structure Name NMR M + H range 2

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-[(4- methoxyphenyl)methyl]-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, CHLOROFORM-d) d7.45 (t, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz,2H), 6.70 (d, J = 8.5 Hz, 2H), 3.79 (s, 6H), 3.77 (s, 3H), 3.73 (s, 2H),2.51 (t, J = 8.0 Hz, 2H), 1.47 (m, 2H), 1.24 (m, 2H), 0.75 (t, J = 7.4Hz, 3H) 3.21 E 425.1 B 3

2-butyl-6- hydroxy-3-(2- methoxyphenyl)- 5-[(4- methoxyphenyl)methyl]-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, CHLOROFORM-d) d7.57-7.51 (m, 1H), 7.36-7.32 (m, 2H), 7.15- 7.12 (m, 2H), 7.10 (d, J =8.5 Hz, 1H), 6.82- 6.77 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.76- 3.67(m, 2H), 2.67-2.59 (m, 1H), 2.51-2.44 (m, 1H), 1.56-1.46 (m, 2H),1.29-1.19 (m, 3H), 0.75 (t, J = 7.3 Hz, 3H) 3.25 E 395.1 C 4

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (1,2,4-oxadiazol-3-yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 9.67 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 8.5 Hz,2H), 7.42 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.75 (s, 6H),3.69 (s, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H), 1.16 (m, 2H), 0.72(t, J = 7.3 Hz, 3H) 1.57 A 463.2 A 5

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (1H-pyrazol-1-yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 8.40 (s, 1H), 7.71 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H), 7.43(t, J = 7.4 Hz, 1H), 7.34 (d, J = 7.3 Hz, 2H), 6.82 (d, J = 6.8 Hz, 2H),6.51 (s, 1H), 3.76 (s, 6H), 3.61 (s, 2H), 2.16 (t, J = 7.6 Hz, 2H), 1.43(m, 2H), 1.15 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H) 1.53 A 461.5 A 6

2-butyl-3-(2,6- dimethoxyphenyl)- 5-{[2-fluoro-4- (1,2,4-oxadiazol-3-yl)phenyl]methyl}- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 9.73 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 9.5Hz, 1H), 7.45 (t, J = 8.5 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.84 (d, J= 8.5 Hz, 2H), 3.77 (s, 6H), 3.71 (s, 2H), 2.23 (t, J = 7.6 Hz, 2H),1.47 (m, 2H), 1.18 (m, 2H), 0.73 (t, J = 7.6 Hz, 3H) 1.64 A 480.9 A 7

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-[(4- methanesulfonyl-phenyl) methyl]-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) d7.81 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 8.5 Hz,1H), 6.84 (d, J = 8.5 Hz, 2H), 3.75 (s, 6H), 3.70 (s, 2H), 3.17 (s, 3H),2.20 (t, J = 7.6 Hz, 2H), 1.44 (m, 2H), 1.16 (m, 2H), 0.72 (t, J = 7.3Hz, 3H) 1.35 A 473.2 B 8

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-[(5- methyl-1,2-oxazol-3-yl)methyl]-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) d7.46 (t, J = 8.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 2H), 5.91 (s, 1H), 3.76(s, 6H), 3.55 (s, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H), 1.16 (m,2H), 0.72 (t, J = 7.6 Hz, 3H) 1.29 A 400.1 B 9

N-(4-{[2- butyl-1-(2,6- dimethoxyphenyl)- 4-hydroxy-6- oxo-1,6-dihydropyrimidin- 5-yl]methyl} phenyl) acetamide 1H NMR (500 MHz,DMSO-d6) d 7.45 (t, J = 8.5 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.13 (d,J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 3.74 (s, 6H), 3.53 (s, 2H),2.18 (t, J = 7.6 Hz, 2H), 2.02 (s, 3H), 1.44 (m, 2H), 1.15 (m, 2H), 0.72(t, J = 7.0 Hz, 3H) 1.32 A 452.1 B 10

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 7.98 (d, J = 18.2 Hz, 2H), 7.44-7.46 (m, 3H), 6.84 (d, J= 8.2 Hz, 2H), 3.74 (s, 6H), 3.70 (s, 2H), 2.41 (s, 3H), 2.19 (t, J =7.3 Hz, 2H), 1.44 (m, 2H), 1.15 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H) 1.65 A477.1 A 11

2-butyl-5-{[2-(4- chlorophenyl)-1,3- oxazol-4-yl] methyl}-3-(2,6-dimethoxyphenyl)- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 7.95 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.60 (d, J = 8.5Hz, 2H), 7.45 (t, J = 8.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 3.76 (s,6H), 3.56 (s, 2H), 2.21 (t, J = 7.3 Hz, 2H), 1.46 (m, 2H), 1.17 (m, 2H),0.73 (t, J = 7.3 Hz, 3H) 1.82 A 496.0 A 12

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (1,2,3-thiadiazol-4-yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 9.53 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.46 (t, J = 8.5 Hz,1H), 7.40 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 3.76 (s, 6H),3.68 (s, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H), 1.16 (m, 2H), 0.72(t, J = 7.3 Hz, 3H) 1.64 A 479.1 A 13

2-butyl-3-(2,6- dimethoxyphenyl)- 5-{[3-fluoro-4- (1,2,4-oxadiazol-3-yl)phenyl]methyl}- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 9.73 (s, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 8.5Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 11.9 Hz, 1H), 6.85 (d, J= 8.5 Hz, 2H), 3.76 (s, 6H), 3.70 (s, 2H), 2.22 (t, J = 7.6 Hz, 2H),1.45 (m, 2H), 1.16 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H) 1.55 A 481.2 A 14

2-butyl-5-{[6-(4- chlorophenyl) pyridin- 3-yl]methyl}- 3-(2,6-dimethoxyphenyl)- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 8.53 (s, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 7.9Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.46 (t, J= 8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 3.75 (s, 6H), 3.65 (s, 2H),2.21 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H), 1.16 (m, 2H), 0.72 (t, J = 7.3Hz, 3H) 1.90 A 506.1 A 15

4-{[2-butyl-1-(2,6- dimethoxyphenyl)- 4-hydroxy-6- oxo-1,6-dihydropyrimidin- 5-yl]methyl}-N- ethylbenzamide 1H NMR (500 MHz,DMSO-d6) d 8.34 (t, J = 5.5 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.45 (t,J = 8.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H),3.75 (s, 6H), 3.64 (s, 2H), 3.25-3.33 (m, 2H), 2.19 (t, J = 7.6 Hz, 2H),1.44 (m, 2H), 1.10-1.18 (m, 5H), 0.72 (t, J = 7.3 Hz, 3H) 1.36 A 466.0 B16

N-(4-{[1-(2,6- dimethoxyphenyl)- 4-hydroxy-2-(3- methylbutyl)-6-oxo-1,6- dihydropyrimidin- 5-yl]methyl} phenyl) acetamide 1H NMR (500MHz, DMSO-d6) d 9.82 (s, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.41 (d, J = 7.9Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.74 (s,6H), 3.53 (s, 2H), 2.17 (t, J = 7.9 Hz, 2H), 2.01 (s, 3H), 1.32-1.37 (m,3H), 0.67 (d, J = 5.5 Hz, 6H) 1.46 A 466.2 B 17

3-(2,6- dimethoxyphenyl)- 6-hydroxy-2-(3- methylbutyl)- 5-{[4-(1,2,4-oxadiazol-3- yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 9.67 (s, 1H), 7.94 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 7.9Hz, 2H), 7.46 (t, J = 8.2 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 3.76 (s,6H), 3.68 (s, 2H), 2.20 (m, 2H), 1.35 (m, 3H), 0.67 (d, J = 4.3 Hz, 6H)1.67 A 477.2 B 18

5-{[2-(4- chlorophenyl)- 1,3-oxazol- 4-yl]methyl}- 3-(2,6-dimethoxyphenyl)- 6-hydroxy-2-(3- methylbutyl)-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) d 7.95 (d, J = 8.2 Hz, 2H), 7.60 (s,1H), 7.60 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 8.5 Hz, 1H), 6.84 (d, J =8.5 Hz, 2H), 3.76 (s, 6H), 3.56 (s, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.36(m, 3H), 0.69 (d, J = 5.5 Hz, 6H) 1.89 A 510.0 B 19

5-benzyl-2- butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-3,4-dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) d 7.45 (t, J = 8.5 Hz,1H), 7.23 (m, 4H), 7.14 (m, 1H), 6.84 (d, J = 8.5 Hz, 2H), 3.75 (s, 6H),3.60 (s, 2H), 2.19 (t, J = 7.6 Hz, 2H), 1.44 (m, 2H), 1.16 (m, 2H), 0.72(t, J = 7.3 Hz, 3H) 1.59 A 394.9 B 20

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5- ({3-[4- (trifluoromethyl)phenyl]-1,2,4- oxadiazol-5-yl} methyl)-3,4- dihydropyrimidin- 4-one 1HNMR (500 MHz, DMSO-d6) d 8.29 (d, J = 8.2 Hz, 2H), 8.00 (d, J = 8.2 Hz,2H), 7.45 (t, J = 8.2 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 3.82 (s, 2H),3.75 (s, 6H), 2.23 (t, J = 7.3 Hz, 2H), 1.47 (m, 2H), 1.18 (m, 2H), 0.73(t, J = 7.3 Hz, 3H) 1.81 A 531.1 A 21

3-(2,6- dimethoxyphenyl)- 6-hydroxy-2-(3- methylbutyl)-5-{[5-(4-methylphenyl)- 1,3,4-oxadiazol-2- yl]methyl}-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) d 7.81 (d, J = 7.9 Hz, 2H), 7.45 (t, J =8.5 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.90(s, 2H), 3.75 (s, 6H), 2.40 (s, 3H), 2.21 (m, 2H), 1.36 (m, 3H), 0.68(d, J = 5.5 Hz, 6H) 1.66 A 491.1 B 22

2-butyl-5-{[2-(4- chlorophenyl)-1,3- thiazol-4-yl] methyl}-3-(2,6-dimethoxyphenyl)- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 7.93 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.46(t, J = 8.5 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J = 8.5 Hz, 2H), 3.80 (s,2H), 3.77 (s, 6H), 2.22 (t, J = 7.6 Hz, 2H), 1.47 (m, 2H), 1.18 (m, 2H),0.74 (t, J = 7.0 Hz, 3H) 1.98 A 512.3 B 23

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[2- (4-methylphenyl)-1,3-thiazol-4-yl] methyl}-3,4- dihydropyrimidin- 4-one `H NMR (500 MHz,DMSO-d6) d 7.80 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 8.2 Hz, 1H), 7.31 (d,J = 7.9 Hz, 2H), 6.91 (s, 1H), 6.85 (d, J = 8.5 Hz, 2H), 3.78 (s, 2H),3.77 (s, 6H), 2.22 (t, J = 7.6 Hz, 2H), 1.47 (m, 2H), 1.18 (m, 2H), 0.73(t, J = 7.0 Hz, 3H) 1.88 B 492.0 B 24

2-butyl-5-{[1-(4 -chlorophenyl)-1H- pyrazol-3-yl] methyl}-3-(2,6-dimethoxyphenyl)- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 8.33 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2Hz, 2H), 7.45 (t, J = 8.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.21 (s,1H), 3.76 (s, 6H), 3.58 (s, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H),1.16 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H) 1.94 B 495.0 A 25

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[1- (4-methylphenyl)-1H-pyrazol-4-yl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 8.07 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.47 (s, 1H), 7.45(t, J = 8.2 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H),3.75 (s, 6H), 3.48 (s, 2H), 2.33 (s, 3H), 2.19 (t, J = 7.3 Hz, 2H), 1.45(m, 2H), 1.16 (m, 2H), 0.72 (t, J = 7.0 Hz, 3H) 1.75 A 475.1 A 26

2-butyl-5-{[2-(4- chlorophenyl)- 1,3- thiazol-5-yl] methyl}- 3-(2,6-dimethoxyphenyl)- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 7.87 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.54 (d, J = 8.2Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 3.79 (s,2H), 3.74 (s, 6H), 2.14 (t, J = 7.6 Hz, 2H), 1.42 (m, 2H), 1.14 (m, 2H),0.71 (t, J = 7.0 Hz, 3H) 1.96 A 511.9 A 27

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (1H-pyrazol-1-ylmethyl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 7.78 (s, 1H), 7.45 (s, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.18(d, J = 7.3 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H),6.26 (s, 1H), 5.26 (s, 2H), 3.74 (s, 6H), 3.57 (s, 2H), 2.18 (t, J = 7.3Hz, 2H), 1.44 (m, 2H), 1.15 (m, 2H), 0.72 (t, J = 7.0 Hz, 3H) 1.57 A475.1 A 28

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (2-oxo-1,2-dihydropyridin-1- yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR(500 MHz, DMSO-d6) d 7.63 (d, J = 6.1 Hz, 1H), 7.50 (t, J = 7.3 Hz, 1H),7.46 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.5 Hz,2H), 6.85 (d, J = 7.9 Hz, 2H), 6.47 (d, J = 9.2 Hz, 1H), 6.30 (t, J =5.5 Hz, 1H), 3.76 (s, 6H), 3.66 (s, 2H), 2.20 (t, J = 7.3 Hz, 2H), 1.45(m, 2H), 1.16 (m, 2H), 0.72 (t, J = 7.0 Hz, 3H) 1.43 A 488.1 A 29

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5- {[6-(4- methoxyphenyl)pyridin-3- yl]methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 8.45 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.3 Hz,2H), 7.46 (t, J = 8.5 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 6.91 (d, J =8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 3.90 (s, 3H), 3.76 (s, 6H), 3.64(s, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.45 (m, 2H), 1.16 (m, 2H), 0.72 (t,J = 7.0 Hz, 3H) 1.84 A 502.1 A 30

5-[(1-benzyl-1H- pyrazol-4- yl)methyl]-2- butyl-3-(2,6-dimethoxyphenyl)- 6-hydroxy-3,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) d 7.43-7.46 (m, 2H), 7.2-7.35 (m, 3H), 7.21-7.23 (m, 3H),6.84 (d, J = 8.5 Hz, 2H), 3.73 (s, 8H), 2.17 (t, J = 7.3 Hz, 2H), 1.44(m, 2H), 1.15 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H) 1.62 A 475.1 A 31

5-{[1-(4- chlorophenyl)- 1H-pyrazol- 3-yl]methyl}- 3-(2,6-dimethoxyphenyl)- 2-(ethoxymethyl)- 6-hydroxy-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) d 8.36 (s, 1H), 7.82 (d, J = 8.2 Hz,2H), 7.53 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 8.5 Hz, 1H), 6.83 (d, J =8.2 Hz, 2H), 6.22 (s, 1H), 3.95 (s, 2H), 3.76 (s, 6H), 3.68 (s, 2H),3.29 (q, J = 7.0 Hz, 2H), 0.99 (t, J = 7.0 Hz, 3H) 1.54 A 496.9 B 32

3-(2,6- dimethoxyphenyl)- 2-(ethoxymethyl)- 6-hydroxy-5-{[4-(1,2,4-oxadiazol-3- yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1HNMR (500 MHz, DMSO-d6) d 9.68 (s, 1H), 7.95 (d, J = 7.6 Hz, 2H),7.452-7.46 (m, 3H), 6.83 (d, J = 8.5 Hz, 2H), 3.95 (s, 2H), 3.76 (s,6H), 3.72 (s, 2H), 3.26-3.34 (m, 2H), 0.98 (t, J = 6.7 Hz, 3H) 1.36 A465.3 B 33

5-{[2-(4- chlorophenyl)- 1,3-oxazol- 4-yl]methyl}- 3-(2,6-dimethoxyphenyl)- 2-(ethoxymethyl)- 6-hydroxy-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) d 7.95 (d, J = 8.5 Hz, 2H), 7.63 (s,1H), 7.60 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 8.5 Hz, 1H), 6.83 (d, J =8.5 Hz, 2H), 3.95 (s, 2H), 3.76 (s, 6H), 3.59 (s, 2H), 3.30 (q, J = 7.0Hz, 2H), 0.99 (t, J = 7.0 Hz, 3H) 1.6 A 498.0 B 34

3-(2,6- dimethoxyphenyl)- 6-hydroxy-2-(3- methylbutyl)- 5-{[4-(2-oxo-1,2- dihydropyridin-1- yl)phenyl] methyl}-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) d 7.62 (dd, J = 1.8, 6.7 Hz, 1H), 7.50(dt, J = 1.8, 6.7 Hz, 1H), 7.44 (t, J = 8.5 Hz, 1H), 7.35 (d, J = 8.2Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.47 (d, J= 9.2 Hz, 1H), 6.30 (t, J = 7.6 Hz, 1H), 3.75 (s, 6H), 3.65 (s, 2H),2.17 (t, J = 7.0 Hz, 2H), 1.33-1.37 (m, 3H), 0.68 (d, J = 6.1 Hz, 6H)1.58 A 502.1 A 35

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (2-oxopiperidin-1-yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 7.45 (t, J = 8.5 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.11 (d,J = 8.2 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.75 (s, 6H), 3.58 (s, 2H),3.56 (t, J = 6.1 Hz, 2H), 2.36- 2.40 (m, 2H), 2.19 (t, J = 7.6 Hz, 2H),1.84 (m, 4H), 1.44 (m, 2H), 1.15 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H) 1.55A 492.1 A 36

2-butyl-3-(2,6- dimethoxyphenyl)- 6-hydroxy-5-{[4- (morpholin-4-yl)phenyl] methyl}-3,4- dihydropyrimidin- 4-one 1H NMR (500 MHz,DMSO-d6) d 7.41 (t, J = 8.2 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.81 (d,J = 8.2 Hz, 2H), 6.79 (d, J = 7.9 Hz, 2H), 3.74 (s, 6H), 3.72 (s, 2H),3.16-3.20 (m, 2H), 3.01-3.03 (m, 2H), 2.11 (t, J = 7.6 Hz, 2H), 1.59 (m,2H), 1.42 (m, 2H), 1.33 (m, 2H), 1.14 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H)1.56 A 480.1 A

Example 373-(2,6-dimethoxyphenyl)-5-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)benzyl)-2-(4-fluorophenyl)-6-hydroxypyrimidin-4(3B)-one

Compound 37a. N-(2,6-dimethoxyphenyl)-4-fluorobenzimidamide

To a solution of 2,6-dimethoxyaniline (0.5 g, 3 mmol) and4-fluorobenzonitrile (0.5 g, 4 mmol) in toluene (10 ml) at 0° C. wasadded dropwise TMS-OTf (0.65 ml, 3.6 mmol). The resulting mixture wasstirred at 0° C. for 10 min and heated to 110° C. for 15 hrs. Thereaction mixture was cooled to 0° C., quenched with 1.5 M Na₂HPO₄ (10mL) solution and diluted with EtOAc. The organic layer was washed with1.5 M Na₂HPO₄ solution and dried over sodium sulfate, concentrated togive a brown oil. The residue was purified by a silica gel (80 g) columnand was eluted with 0-100% 0.5% TEA/EtOAc in DCM. Fractions containingcompound 37a were combined and the solvent removed to give 37a (0.55 g,2.0 mmol, 61% yield) an off white solid. 1H NMR (500 MHz, CDCl₃) δ 7.96(br s, 2H), 7.10 (br s, 2H), 7.02 (t, J=8.0 Hz, 1H), 6.64 (d, J=7.7 Hz,2H), 4.68 (br s, 2H), 3.80 (s, 6H).

Compound 37b.1-(2,6-dimethoxyphenyl)-2-(4-fluorophenyl)-6-hydroxypyrimidin-4(1H)-one

To a mixture of Compound 37a (50 mg, 0.18 mmol) and diethyl malonate (44mg, 0.27 mmol) in TEA (1.0 ml, 7.3 mmol) was added TMS-Cl (0.35 ml, 2.7mmol) at 0° C. The mixture was stirred at RT for 10 min and heated to100° C. for 3 d. The reaction mixture was concentrated in vacuo anddiluted with EtOAc. The organic layer was washed with 0.1M HCL. Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The residue was added to a silica gel (12 g) column and was eluted with10-90% EtOAc in hexanes. Fractions containing Compound 37b were combinedand the solvent removed to yield a yellow solid (25 mg, 0.07 mmol, 40%yield). 1H NMR (500 MHz, CDCl₃) δ 7.31 (dd, J=5.3, 8.8 Hz, 2H), 7.21 (t,J=8.6 Hz, 2H), 6.90 (t, J=8.6 Hz, 1H), 6.45 (d, J=8.6 Hz, 2H), 5.67 (s,1H), 3.72 (s, 6H).

Compound 37c. 5-fluoro-1-(4-(hydroxymethyl)phenyl)pyridin-2(1)-one

To a mixture of (4-iodophenyl)methanol (250 mg, 1.07 mmol) and5-fluoropyridin-2-ol (121 mg, 1.07 mmol) in dioxane (2 mL) was addedC_(S2)CO₃ (696 mg, 2.14 mmol) and N, N-dimethylethylenediamine (141 mg,1.60 mmol). The mixture was degassed with argon for 20 min. Copper (I)iodide (203 mg, 1.07 mmol) was added and the reaction mixture was heatedto 115° C. for 16 hrs. The reaction mixture was allowed to cool to RT,filtered and concentrated in vacuo. The residue was added to a silicagel (40 g) column and was eluted with 0-20% MeOH in DCM. Fractionscontaining Compound 37c were combined and the solvent removed to yieldan off white solid (46 mg, 0.21 mmol, 21% yield). 1H NMR (500 MHz,CDCl₃) δ 7.53 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.37-7.40 (m,1H), 7.31 (t, J=4.0 Hz, 1H), 6.66 (dd, J=5.4, 9.5 Hz, 1H), 4.79 (s, 2H).

Compound 37d. 1-(4-(chloromethyl)phenyl)-5-fluoropyridin-2(1B)-one

To a stirred solution of Compound 37c (46 mg, 0.21 mmol) in CHCl₃ (5 mL)was added thionyl chloride (0.05 mL, 0.6 mmol). The reaction mixture washeated to 35° C. for 2 hrs. The reaction mixture was concentrated invacuo and diluted with DCM. The organic layer was washed with satNaHCO₃. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was added to a silica gel (12 g)column and was eluted with 0-100% EtOAc in hexanes. Fractions containingCompound 37c were combined and the solvent removed to yield a whitesolid (40 mg, 0.17 mmol, 80% yield). 1H NMR (500 MHz, CDCl₃) δ 7.55 (d,J=8.5 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.39 (dd, J=3.5, 6.9 Hz, 1H),7.28-7.31 (m, 1H), 6.67 (dd, J=4.7, 9.4 Hz, 1H), 4.65 (s, 2H).

Example 37.3-(2,6-dimethoxyphenyl)-5-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)benzyl)-2-(4-fluorophenyl)-6-hydroxypyrimidin-4(3H)-one

To a suspension of Compound 37b (15 mg, 0.040 mmol) and Compound 37d(12.5 mg, 0.0530 mmol) in acetone (1 mL) and water (0.1 mL) was addedlithium carbonate (6.48 mg, 0.0880 mmol) and TBAI (8.09 mg, 0.0220mmol). The reaction mixture was stirred at RT for 5 d. The reactionmixture was concentrated under reduced pressure and filtered. Theresidue was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10 mM ammonium acetate; Gradient: 10-55% Bover 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing Example 37 were combined and dried via centrifugalevaporation to give a white solid (2.2 mg, 10% yield). The estimatedpurity by LCMS analysis was 95%, HPLC method A, Rt=1.28 min, MSm/z=544.3 (M+H). 1H NMR (500 MHz, DMSO-d6) 7.90 (br s, 1H), 7.65 (br s,1H), 7.41 (br s, 2H), 7.22-7.34 (m, 5H), 7.06 (br s, 2H), 6.60 (d, J=7.3Hz, 2H), 6.50 (dd, J=4.9, 10.0 Hz, 1H), 3.72 (s, 2H), 3.66 (s, 6H).Human APJ cAMP EC₅₀ potency range: A.

Examples 38 to 60 were prepared as described in the general proceduregiven for Example 1.

Rt(min) APJ cAMP method Potency Ex# Structure Name NMR M + H range 38

2-cyclopentyl-3-(2,6- dimethoxyphenyl)-6- hydroxy-5-{[4-(2-oxo-1,2-dihydropyridin-1- yl)phenyl]methyl}-3,4- dihydropyrimidin-4-one 1H NMR(500 MHz, DMSO-d6) Shift 7.62 (br d, J = 6.7 Hz, 1H), 7.50 (br t, J =7.2 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.35 (br d, J = 8.2 Hz, 2H), 7.26(d, J = 8.2 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.47 (d, J = 9.2 Hz, 1H),6.30 (t, J = 6.6 Hz, 1H), 3.75 (s, 6H), 3.67 (s, 2H), 3.26-3.08 (m, 1H),1.89-1.50 (m, 4H), 1.46-1.22 (m, 4H) 1.53, A, 500.1 A 39

2-(cyclobutoxymethyl)-3- (2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.62 (br d, J =6.4 Hz, 1H), 7.50 (br t, J = 7.2 Hz, 1H), 7.42 (br t, J = 8.4 Hz, 1H),7.35 (br d, J = 7.9 Hz, 2H), 7.25 (br d, J = 8.2 Hz, 2H), 6.80 (d, J =8.5 Hz, 2H), 6.46 (br d, J = 9.2 Hz, 1H), 6.29 (br t, J = 6.7 Hz, 1H),3.80 (s, 2H), 3.74 (s, 7H), 3.66 (s, 2H), 2.05-1.86 (m, 2H), 1.68-1.46(m, 3H), 1.43-1.24 (m, 1H) 1.42, A, 516.1 A 40

2-(cyclopropoxymethyl)-3- (2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.42 (br d, J =6.7 Hz, 1H), 7.36-7.28 (m, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.15 br d, J =8.2 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 6.27(d, J = 9.5 Hz, 1H), 6.10 (t, J = 6.4 Hz, 1H), 3.74 (s, 2H), 3.55 (s,6H), 3.48 (s, 2H), 3.09 (dt, J = 5.9, 3.0 Hz, 1H), 0.22- 0.06 (m, 2H),0.00 (br s, 2H) 1.27, A, 502.1 A 41

2-(2-cyclopropylethyl)-3- (2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.82 (br d, J =6.1 Hz, 1H), 7.77-7.62 (m, 2H), 7.55 (br d, J = 7.9 Hz, 2H), 7.46 (br d,J = 7.9 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 9.2 Hz, 1H),6.53 (t, J = 6.7 Hz, 1H), 3.96 (s, 6H), 3.86 (s, 2H), 2.49 (br t, J =7.8 Hz, 2H), 1.67-1.47 (m, 2H), 0.80 (br s, 1H), 0.50 (br d, J = 7.6 Hz,2H), 0.01 (br d, J = 4.6 Hz, 2H) 1.76, A, 500.1 A 42

2-butyl-5-{[4-(4-chloro-2- oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3-(2,6- dimethoxyphenyl)-6- hydroxy-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.71 (d, J = 7.3Hz, 1H), 7.50-7.32 (m, 3H), 7.20 (br d, J = 7.9 Hz, 2H), 6.79 (d J = 8.5Hz, 2H), 6.62 (s, 1H), 6.43 (br d, J = 6.1 Hz, 1H), 3.73 (s, 6H), 3.60(s, 2H), 2.08 (br t, J = 7.6 Hz, 2H), 1.49- 1.37 (m, 2H), 1.20-1.04 (m,2H), 0.70 (t, J = 7.2 Hz, 3H) 1.76, A, 522.0 A 43

2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxy-5-{[4-(4-methyl-2-oxo-1,2-dihydropyridin- 1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.50 (d, J = 6.7Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.32 (br d, J = 7.9 Hz, 2H),7.26-7.20 (m, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.28 (s, 1H), 6.17 (br d, J= 7.0 Hz, 1H), 3.75 (s, 6H), 3.65 (s, 2H), 2.28- 2.14 (m, 5H), 1.44(quin, J = 7.5 Hz, 2H), 1.15 (sxt, J = 7.3 Hz, 2H), 0.71 (t, J = 7.3 Hz,3H) 1.49, A, 502.0 A 44

2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxy-5-{[4-(6- methylpyridin-3-yl)phenyl]methyl}-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6)Shift 8.88 (s, 1H), 8.29 (br d, J = 8.5 Hz, 1H), 7.75-7.57 (m, 3H), 7.46(br t, J = 8.2 Hz, 1H), 7.37 (br d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.5Hz, 2H), 3.76 (s, 6H), 3.66 (s, 2H), 2.62 (s, 3H), 2.20 (br t, J = 7.3Hz, 2H), 1.49-1.40 (m, 2H), 1.21-1.10 (m, 2H), 0.72 (t, J = 7.5 Hz, 3H)1.86, A, 485.9 B 45

5-({[1,1′-biphenyl]-4- yl}methyl)-2-butyl-3-(2,6- dimethoxyphenyl)-6-hydroxy-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.62(br d, J = 7.6 Hz, 2H), 7.53 (br d, J = 7.9 Hz, 2H), 7.44 (br t, J = 7.3Hz, 3H), 7.37-7.26 (m, 3H), 6.83 (d, J = 8.5 Hz, 2H), 3.74 (s, 6H), 3.56(br s, 2H), 2.19 (br t, J = 7.6 Hz, 2H), 1.43 (quin, J = 7.4 Hz, 2H),1.14 (sxt, J = 7.3 Hz, 2H), 0.70 (t, J = 7.2 Hz, 3H) 1.95, A, 471.2 A 46

2-butyl-5-{[4-(5- chloropyridin-2- yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6- hydroxy-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz,CHLOROFORM-d) Shift 8.61 (dd, J = 2.5, 0.8 Hz, 1H), 7.84 (d, J = 8.5 Hz,2H), 7.74-7.66 (m, 1H), 7.66-7.60 (m, 1H), 7.55-7.50 (m, 2H), 7.41 (t, J= 8.5 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 3.88 (s, 2H), 3.80 (s, 6H),2.45-2.31 (m, 2H), 1.51-1.40 (m, 2H), 1.35- 1.18 (m, 2H), 0.79 (t, J =7.4 Hz, 3H) 2.10, A, 506.1 A 47

2-butyl-3-(2,6- dimethoxyphenyl)-5-{[4- (5-fluoro-2-oxo-1,2-dihydropyridin-1- yl)phenyl]methyl}-6- hydroxy-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.87 (br s, 1H),7.65 (br t, J = 8.2 Hz, 1H), 7.43 (br t, J = 8.2 Hz, 1H), 7.35 (br d, J= 7.6 Hz, 2H), 7.26 (br d, J = 7.9 Hz, 2H), 6.82 (br d, J = 8.5 Hz, 2H),6.50 (br dd, J = 10.1, 5.5 Hz, 1H), 3.74 (s, 6H), 3.64 (s, 2H), 2.16 (brt, J = 7.5 Hz, 2H), 1.42 (quin, J = 7.5 Hz, 2H), 1.14 (dq, J = 14.7, 7.4Hz, 2H), 0.70 (br t, J = 7.2 Hz, 3H) 1.43, A, 505.9 A 48

2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxy-5-{[4-(2- methoxypyridin-3-yl)phenyl]methyl}-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6)Shift 8.15 (dd, J = 4.9, 1.5 Hz, 1H), 7.70 (dd, J = 7.3, 1.8 Hz, 1H),7.49-7.35 (m, 3H), 7.29 (br d, J = 8.2 Hz, 2H), 7.08 (dd, J = 1.2, 5.0Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 3.87 (s, 2H), 3.74 (s, 6H), 3.61 (s,3H), 2.15 (br t, J = 7.6 Hz, 2H), 1.43 (quin, J = 7.6 Hz, 2H), 1.14(sxt, J = 7.3 Hz, 2H), 0.71 (t, J = 7.3 Hz, 3H) 1.80, A, 502.2 A 49

2-butyl-5-{[4-(5-chloro-2- oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3-(2,6- dimethoxyphenyl)-6- hydroxy-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.90 (d, J = 2.7Hz, 1H), 7.56 (dd, J = 9.8, 3.1 Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 7.35(d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H),6.51 (d, J = 9.8 Hz, 1H), 3.74 (s, 6H), 3.64 (s, 2H), 2.15 (br t, J =7.6 Hz, 2H), 1.43 (quin, J = 7.5 Hz, 2H), 1.14 (sxt, J = 7.4 Hz, 2H),0.71 (t, J = 7.3 Hz, 3H) 1.55, A, 522.1 A 50

2-butyl-3-(2,6- dimethoxyphenyl)-6- hydroxy-5-{[4-(5-methyl-2-oxo-1,2-dihydropyridin- 1-yl)phenyl]methyl}-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.53-7.35 (m,3H), 7.33 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.84 (d, J =8.5 Hz, 2H), 6.41 (d, J = 9.2 Hz, 1H), 3.75 (s, 6H), 3.65 (s, 2H), 2.19(t, J = 7.6 Hz, 2H), 1.92 (s, 3H), 1.44 (quin, J = 7.6 Hz, 2H), 1.15(sxt, J = 7.4 Hz, 2H), 0.71 (t, J = 7.3 Hz, 3H) 1.47, A, 501.9 A 51

2-cyclopentyl-3-(2,6- dimethoxyphenyl)-5-{[4- (5-fluoro-2-oxo-1,2-dihydropyridin-1- yl)phenyl]methyl}-6- hydroxy-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.87 (t, J = 4.0Hz, 1H), 7.64 (ddd, J = 10.1, 7.0, 3.4 Hz, 1H), 7.44-7.30 (m, 3H), 7.20(d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.2 Hz, 2H), 6.49 (dd, J = 10.1, 5.5Hz, 1H), 3.71 (s, 6H), 3.62-3.53 (m, 2H), 2.42 (quin, J = 8.3 Hz, 1H),1.85- 1.70 (m, 4H), 1.47 (br d, J = 7.6 Hz, 4H) 1.59, A, 517.9 A 52

3-(2,6-dimethoxyphenyl)- 5-{[4-(5-fluoro-2-oxo-1,2- dihydropyridin-1-yl)phenyl]methyl}-6- hydroxy-2-(3- methylbutyl)-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.89 (t, J = 4.0Hz, 1H), 7.65 (ddd, J = 10.1, 7.1, 3.2 Hz, 1H), 7.47-7.31 (m, 3H), 7.24(d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.49 (dd, J = 10.1, 5.5Hz, 1H), 3.74 (s, 6H), 3.61 (s, 2H), 2.16-2.01 (m, 2H), 1.68-1.50 (m,2H), 1.32 (dq, J = 14.6, 7.1 Hz, 1H), 0.95 (t, J = 7.3 Hz, 6H) 1.55, A,520.2 A 53

5-{[4-(5-chloro-2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6- hydroxy-2-(3- methylbutyl)-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.89 (d, J = 2.7Hz, 1H), 7.56 (dd, J = 9.8, 2.7 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.35(br d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 8.5 Hz,2H), 6.51 (d, J = 9.8 Hz, 1H), 3.74 (s, 6H), 3.62 (s, 2H), 2.21-2.05 (m,2H), 1.56 (br d, J = 7.3 Hz, 2H), 1.40-1.23 (m, 1H), 0.94 (t, J = 7.3Hz, 6H) 1.66, A, 535.9 A 54

3-(2,6-dimethoxyphenyl)- 6-hydroxy-5-{[4-(5- methyl-2-oxo-1,2-dihydropyridin-1- yl)phenyl]methyl}-2-(3- methylbutyl)-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.50-7.31 (m,5H), 7.18 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.41 (d, J =9.2 Hz, 1H), 3.73 (s, 6H), 3.60 (s, 2H), 2.16-2.06 (m, 2H), 2.04 (s,3H), 1.67-1.50 (m, 2H), 1.42-1.24 (m, 1H), 0.95 (t, J = 7.3 Hz, 6H)1.57, A, 516.2 A 55

2-(2-cyclopropylethyl)-3- (2,6-dimethoxyphenyl)-6-hydroxy-5-{[4-(5-methyl- 2-oxo-1,2-dihydropyridin-1-yl)phenyl]methyl}-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz,DMSO-d6) Shift 7.67 (t, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.59 (dd, J =9.5, 2.1 Hz, 1H), 7.53 (br d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H),7.06 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 9.5 Hz, 1H), 3.96 (s, 6H), 3.86(s, 2H), 2.50 (br t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.63-1.50 (m, 2H),0.89-0.73 (m, 1H), 0.56-0.44 (m, 2H), 0.00 (br d, J = 4.3 Hz, 2H) 1.48,A, 514.2 A 56

2-(2-cyclopropylethyl)-3- (2,6-dimethoxyphenyl)-5-{[4-(5-fluoro-2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-6-hydroxy-3,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.11(t, J = 4.0 Hz, 1H), 7.88 (ddd, J = 10.l, 7.0, 3.1 Hz, 1H), 7.66 (t, J =8.4 Hz, 1H), 7.57 (br d, J = 8.2 Hz, 2H), 7.48 (br d, J = 8.2 Hz, 2H),7.05 (d, J = 8.5 Hz, 2H), 6.72 (dd, J = 10.1, 5.5 Hz, 1H), 3.96 (s, 6H),3.85 (s, 2H), 2.54-2.40 (m, 2H), 1.79 (br d, J = 7.0 Hz, 2H), 0.91-0.72(m, 1H), 0.61- 0.43 (m, 2H), 0.00 (br d, J = 4.3 Hz, 2H) 1.44, A, 518.2A 57

5-{[4-(5-chloro-2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-2-(2-cyclopropylethyl)-3-(2,6- dimethoxyphenyl)-6- hydroxy-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.12 (d, J = 2.7Hz, 1H), 7.80 (dd, J = 9.8 2.7 Hz, 1H), 7.69-7.55 (m, 3H), 7.46 (d, J =8.2 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 9.8 Hz, 1H), 3.97(s, 6H), 3.85 (s, 2H), 2.50-2.36 (m, 2H), 1.91-1.73 (m, 2H), 0.91-0.72(m, 1H), 0.59-0.44 (m, 2H), 0.00 (q, J = 4.7 Hz, 2H) 1.55, A, 534.4 A 58

3-(2,6-dimethoxyphenyl)- 6-hydroxy-5-{[4-(5- methyl-2-oxo-1,2-dihydropyridin-1- yl)phenyl]methyl}-2- [(propan-2-yloxy)methyl]-3,4-dihydropyrimidin-4- one 1H NMR (500 MHz, DMSO-d6) Shift 7.48-7.40(m, 2H), 7.37 (dd, J = 9.3, 2.1 Hz, 1H), 7.32 (br d, J = 8.2 Hz, 2H),7.24 (br d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.41 (d, J = 9.3Hz, 1H), 3.90 (s, 2H), 3.73 (s, 6H), 3.67 (s, 2H), 3.32-3.21 (m, 1H),2.03 (s, 3H), 0.87 (d, J = 6.1 Hz, 6H) 1.24, A, 518.3 A 59

3-(2,6-dimethoxyphenyl)- 5-{[4-(5-fluoro-2-oxo-1,2- dihydropyridin-1-yl)phenyl]methyl}-6- hydroxy-2-[(propan-2- yloxy)methyl]-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.88 (br t, J =3.7 Hz, 1H), 7.65 (ddd, J = 10.1, 7.0, 3.4 Hz, 1H), 7.43 (br t, J = 8.4Hz, 1H), 7.36-7.30 (m, 2H), 7.30-7.25 (m, 2H), 6.80 (d, J = 8.5 Hz, 2H),6.49 (dd, J = 10.0, 5.4 Hz, 1H), 3.90 (s, 2H), 3.73 (s, 6H), 3.67 (s,2H), 3.26 (dt, J = 11.9, 6.0 Hz, 1H), 0.86 (d, J = 6.0 Hz, 6H) 1.23, A,522.1 A 60

5-{[4-(5-chloro-2-oxo-1,2- dihydropyridin-1- yl)phenyl]methyl}-3-(2,6-dimethoxyphenyl)-6- hydroxy-2-[(propan-2- yloxy)methyl]-3,4-dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 7.86 (d, J = 2.2Hz, 1H), 7.55 (dd, J = 9.8, 2.4 Hz, 1H), 7.39 (br t, J = 8.4 Hz, 1H),7.34 (br d, J = 7.9 Hz, 2H), 7.24 (br d, J = 8.1 Hz, 2H), 6.77 (d, J =8.4 Hz, 2H), 6.51 (d, J = 9.8 Hz, 1H), 3.85 (s, 2H), 3.71 (s, 2H), 3.68(br s, 6H), 3.29- 3.19 (m, 1H), 0.84 (br d, J = 6.0 Hz, 6H) 1.32, A,538.3 A

Example 612-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-(3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)benzyl)-6-hydroxypyrimidin-4(1H)-one

Compound 61a. methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate

To a stirred solution of methyl 1H-pyrazole-3-carboxylate (1.04 g, 8.25mmol), cyclopropylboronic acid (1.42 g, 16.5 mmol) and Na₂CO₃ (1.75 g,16.5 mmol) in DCE (30 mL) at 70° C. was added 2,2′-bipyridine (1.29 g,8.25 mmol) and copper (11) acetate (1.50 g, 8.25 mmol) under air. Thereaction was heated to 70° C. for 8 hrs. The reaction was allowed tocool to RT. 1 mL AcOH was added and the reaction mixture wasconcentrated in vacuo and the residue diluted with EtOAc. The organiclayer was washed with 1M HCl. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The residue was added to a silicagel (120 g) column and eluted with 0-100% EtOAc in hexanes. Fractionscontaining Compound 61a were collected and the solvent removed in vacuoto yield a clear liquid (1.05 g, 6.29 mmol, 76% yield). MS m/z=167.1(M+H). ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=2.4 Hz, 1H), 6.73 (d,J=2.4 Hz, 1H), 3.85 (tt, J=7.4, 3.8 Hz, 1H), 3.78 (s, 3H), 1.13-1.06 (m,2H), 1.06-0.97 (m, 2H).

Compound 61b. 1-cyclopropyl-1H-pyrazole-3-carboxamide

To a stirred solution of Compound 61a (1.01 g, 6.02 mmol) in MeOH (10mL) was added ammonium hydroxide (3.91 mL, 30.1 mmol). The reactionmixture was heated to 100° C. for 16 hrs. The reaction mixture wasallowed to cool to RT. 1 mL AcOH was added and the reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic layer waswashed with sat NH₄Cl. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo to give Compound 61b (0.89 g, 5.89 mmol, 98%yield) as a white solid. MS m/z=152.2 (M+H). ¹H NMR (500 MHz,CHLOROFORM-d) δ 7.49 (d, J=2.5 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 3.65(tt, J=7.3, 3.7 Hz, 1H), 1.21-1.17 (m, 2H), 1.11-1.05 (m, 2H).

Compound 61c. 1-cyclopropyl-1H-pyrazole-3-carbonitrile

A stirred solution of Compound 1b (0.99 g, 6.55 mmol) in POCl₃ (6.10 ml,65.5 mmol) was heated to 95° C. for 2 hrs. The reaction mixture wasallowed to cool to RT and poured into ice-water. NH₄OH was added untilthe pH was neutral. The reaction mixture was diluted with EtOAc. Theorganic layer was washed with H₂O. The organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The residue was added to asilica gel (24 g) column and was eluted with 0-100% EtOAc in hexanes.Fractions containing Compound 61c were collected, combined and thesolvent removed to yield a clear liquid (610 mg, 4.58 mmol, 70% yield).¹H NMR (400 MHz, CHLOROFORM-d) δ 7.52 (d, J=2.4 Hz, 1H), 6.63 (d, J=2.4Hz, 1H), 3.67 (tt, J=7.4, 3.9 Hz, 1H), 1.25-1.16 (m, 2H), 1.13-1.03 (m,2H).

Compound 61d.1-cyclopropyl-N-(2,6-diethylphenyl)-1H-pyrazole-3-carboximidamide

To a solution of 2,6-diethylaniline (684 mg, 4.58 mmol) and Compound 61c(610 mg, 4.58 mmol) in toluene (5 ml) at 0° C. was added dropwiseTMS-OTf (1.08 ml, 5.96 mmol). The resulting mixture was stirred at 0° C.for 10 min and allowed to warm to RT then heated to 110° C. for 16 hrs.The reaction mixture was cooled to 0° C. and water was added dropwise.The reaction mixture was diluted with EtOAc. The organic layer waswashed with sat NaHCO₃. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The residue was added to a silica gel (24 g)column and was eluted with 0-50% 1% TEA/EtOAc in DCM. Fractionscontaining Compound 61d were collected and the solvent removed in vacuoto yield a yellow solid (1.31 g, 4.60 mmol, 100% yield). MS m/z=152.2(M+H). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.53 (d, J=2.5 Hz, 1H),7.16-7.10 (m, 2H), 7.09-7.02 (m, 1H), 6.99 (d, J=2.2 Hz, 1H), 3.66 (tt,J=7.4, 3.8 Hz, 1H), 2.71-2.42 (m, 4H), 1.20 (t, J=7.6 Hz, 6H), 1.23-1.15(m, 2H), 1.13-1.04 (m, 2H).

Compound 61e. diethyl 2-(4-bromo-3-fluorobenzyl)malonate

NaH (0.537 g, 13.4 mmol) was slurried in THF (20 mL) in a 100 mL flaskthat was equipped with a magnetic stirrer and an N₂ inlet. Diethylmalonate (2.33 g, 14.6 mmol) was added dropwise which resulted insignificant evolution of gas. The mixture was stirred at RT for 1 hrfollowed by a drop wise addition of1-bromo-4-(bromomethyl)-2-fluorobenzene (3.01 g, 11.2 mmol) in THF (10mL). The reaction mixture was stirred at RT for 16 hrs. A mix of mono-and bis-alkylated product observed by LCMS. The reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic layer waswashed with sat NH₄Cl. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The residue was added to a silica gel (120 g)column and was eluted with 040% EtOAc in hexanes. Fractions containingCompound 61e were collected, combined and concentrated in vacuo to yielda clear liquid (2.62 g, 7.55 mmol, 67% yield). MS m/z=348.9 (M+H). ¹HNMR (500 MHz, CHLOROFORM-d) δ 7.52-7.41 (m, 1H), 7.02 (dd, J=9.4, 1.9Hz, 1H), 6.91 (dd, J=8.1, 1.8 Hz, 1H), 4.20 (d, J=1.4 Hz, 4H), 3.62 (t,J=7.8 Hz, 1H), 3.20 (d, J=7.7 Hz, 2H), 1.25 (t, J=7.2 Hz, 6H).

Compound 61f. 2-(4-bromo-3-fluorobenzyl)malonic acid

Compound 61e (2.62 g, 7.55 mmol) was dissolved in a mixture of ethanol(12.5 mL) and water (6.25 mL) in a 100 mL flask that was equipped with amagnetic stirrer. KOH (1.48 g, 26.4 mmol) was added and the reactionmixture was stirred for 2 hrs. The reaction mixture was acidified with3N HCl and the aqueous portion extracted with Et₂O (3×). The combinedorganic portions were dried over MgSO₄, filtered and the filtrate wasconcentrated in vacuo to give Compound 61f (1.95 g, 6.70 mmol, 89%yield) as a white solid. MS m/z=315.0 (M+Na). ¹H NMR (400 MHz,METHANOL-d₄) δ 7.50 (t, J=7.8 Hz, 1H), 7.12 (dd, J=9.9, 1.8 Hz, 1H),7.00 (dd, J=8.1, 1.8 Hz, 1H), 3.64 (t, J=7.7 Hz, 1H), 3.14 (d, J=7.9 Hz,2H).

Compound 61g.5-(4-bromo-3-fluorobenzyl)-2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-6-hydroxypyrimidin-4(1H)-one

Compound 61f (97.1 mg, 0.333 mmol) was slurried in DCM (5 mL) in a 25 mLflask that was equipped with a magnetic stirrer and a N₂ inlet. Oxalylchloride (0.333 mL, 0.667 mmol) and DMF (1 drop) were added and thereaction mixture was stirred at RT for 1 hr. To the reaction mixture wasadded Compound 61d (94.2 mg, 0.333 mmol) in DCM (4 mL), followed by Et₃N(0.186 mL, 1.333 mmol). The reaction mixture was stirred for 1 hr, thenconcentrated in vacuo and the residue diluted with EtOAc. The organiclayer was washed with sat NH₄Cl. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The residue was added to a silicagel (12 g) column and was eluted with 0-100% EtOAc in hexanes. Fractionscontaining Compound 61g were collected, combined and concentrated invacuo to yield a light yellow liquid (112 mg, 0.208 mmol, 63% yield. MSm/z=536.9 (M+H). ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.48-7.43 (m, 1H),7.41-7.35 (m, 1H), 7.27-7.22 (m, 5H), 7.14 (dd, J=8.3, 1.9 Hz, 1H), 3.84(s, 2H), 3.66-3.54 (m, 1H), 2.45-2.33 (m, 2H), 2.26 (dq, J=15.1, 7.6 Hz,2H), 1.09 (m, 2H), 1.07-1.05 (m, 2H), 1.05 (t, J=7.6 Hz, 6H).

Example 61.2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-(3-fluoro-4-(2-fluoro-3-methylpyridin-4-yl)benzyl)-6-hydroxypyrimidin-4(1H)-one

A solution of Compound 61g (15 mg, 0.028 mmol),(2-fluoro-3-methylpyridin-4-yl)boronic acid (13 mg, 0.084 mmol) andPd-XPhos G3 (1.772 mg, 2.093 μmol) in THF (1.8 mL) and phosphoric acid,potassium salt (0.5 M aq.) (0.14 mL, 0.070 mmol) was degassed with Arfor 1 min. The reaction mixture was sealed and heated in a microwavereactor at 120° C. for 45 min. The reaction mixture was filtered andconcentrated under reduced pressure. The residue was purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10mM ammonium acetate; Gradient: 10-55% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing Compound 61 werecombined and dried via centrifugal evaporation to give a white solid(2.6 mg, 16.4% yield). The estimated purity by LCMS analysis was 100%,HPLC method A, Rt=2.08 min, MS m/z=568.3 (M+H). ¹H NMR (500 MHz,DMSO-d₆) δ 8.11 (d, J=4.9 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.40-7.26 (m,2H), 7.26-7.02 (m, 5H), 6.20 (d, J=1.8 Hz, 1H), 3.79 (s, 2H), 3.67 (td,J=7.4, 3.8 Hz, 1H), 2.31-2.11 (m, 4H), 2.05 (s, 3H), 0.93 (t, J=7.5 Hz,6H), 0.82-0.70 (m, 2H), 0.61 (br s, 2H). AP cAMP EC₅₀ potency range: A.

Examples 62 to 94 were prepared as described in the general proceduregiven for Example 61.

APJ Rt(min) cAMP method Potency Ex# Structure Name NMR M + H range 62

1-(2,6- dimethoxyphenyl)- 2-(1-ethyl-1H- pyrazol-3-yl)-6-hydroxy-5-{[4-(3- methylpyridin-4- yl)phenyl] methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.47 (s, 1H),8.41 (d, J = 5.0 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.39 (br d, J = 7.9Hz, 2H), 7.31-7.24 (m, 3H), 7.21 (d, J = 4.9 Hz, 1H), 6.64 (d, J = 8.4Hz, 2H), 5.98 (d, J = 1.9 Hz, 1H), 4.05-3.84 (m, 2H), 3.67 (s, 2H), 3.60(s, 6H), 2.27 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H) 1.36, A, 524.1 A 63

1-(2,6- dimethoxyphenyl)- 2-(1-ethyl-1H- pyrazol-3-yl)-5-{[4-(2-fluoro-3- methylpyridin-4- yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.06 (d, J = 5.0Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.46- 7.28 (m, 5H), 7.21 (brd, J =5.0 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 6.01 (d, J = 1.9 Hz, 1H), 3.94(q, J = 7.2 Hz, 2H), 3.78-3.69 (m, 2H), 3.61 (br s, 6H), 2.16 (s, 3H),1.14 (t, J = 7.2 Hz, 3H) 1.61, A, 542.2 A 64

2-butyl-1-(2,6- diethylphenyl)- 5-{[4-(6-fluoro- 2- methylpyridin-3-yl)phenyl] methyl}-6- hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) Shift 7.75 (t, J = 8.2 Hz, 1H), 7.47-7.35 (m, 1H), 7.29(m, 7.8 Hz, 4H), 7.23 (m, 2H), 7.03 (dd, J = 7.9, 2.7 Hz, 1H), 3.69 (s,2H), 2.34 (s, 3H), 2.30 (br dd, J = 15.0, 7.3 Hz, 2H), 2.21- 2.11 (m,2H), 2.07 (br t, J = 7.8 Hz, 2H), 1.55-1.45 (m, 2H), 1.19-1.10 (m, 2H),1.04 (t, J = 7.5 Hz, 6H), 0.72 (t, J = 7.3 2.23, A, 500.3 A Hz, 3H) 65

2-butyl-1-(2,6- diethylphenyl)- 5-{[4-(6- fluoropyridin- 3-yl)phenyl]methyl}-6- hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR (600 MHz,DMSO-d6) Shift 8.50 (d, J = 1.0 Hz, 1H), 8.23 (td, J = 8.1, 2.2 Hz, 1H),7.58 (d, J = 8.1 Hz, 2H), 7.46-7.39 (m, 1H), 7.35-7.27 (m, 4H), 7.25(dd, J = 8.5, 2.4 Hz, 1H), 3.69 (s, 2H), 2.29 (dt, J = 14.6, 7.3 Hz,2H), 2.21-2.11 (m, 2H), 2.11-2.03 (m, 2H), 1.51 (br t, J = 7.4 Hz, 2H),2.14, A, 486.2 A 1.20-1.10 (m, 2H), 1.06 (t, J = 7.5 Hz, 6H), 0.73 (t, J= 7.4 Hz, 3H) 66

2-butyl-1-(2,6- diethylphenyl)- 5-{[4-(2- fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) Shift 7.46-7.38 (m, 1H), 7.36- 7.32 (m, 2H), 7.32-7.26 (m,4H), 7.20 (br d, J = 4.8 Hz, 1H), 3.71 (s, 2H), 2.37- 2.23 (m, 2H),2.21- 2.12 (m, 2H), 2.15 (s, 3H), 2.09 (br t, J = 7.7 Hz, 2H), 1.57-1.44(m, 2H), 1.21-1.11 (m, 2H), 1.04 2.24, A, 500.2 A (t, J = 7.5 Hz, 6H),0.73 (t, J = 7.3 Hz, 3H) 67

2-butyl-5-[(4- cyclopropylphenyl) methyl]-1-(2,6- diethylphenyl)-6-hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) δ7.46-7.35 (m, 1H), 7.27 (d, J = 7.7 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H),6.90 (d, J = 8.0 Hz, 2H), 3.59 (s, 2H), 2.34-2.22 (m, 2H), 2.20- 2.07(m, 2H), 2.04 (m, 2H), 1.87-1.77 (m, 1H), 1.57-1.40 (m, 2H), 1.18-1.09(m, 2H), 1.05 (t, J = 7.5 Hz, 6H), 0.87 (br dd, J = 8.3, 1.9 Hz, 2H),0.72 (t, J = 7.3 Hz, 3H), 0.62- 2.33, B, 431.3 A 0.53 (m, 2H) 68

5-({[1,1′- biphenyl]-4- yl}methyl)-2- butyl-1-(2,6- diethylphenyl)-6-hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) δ 7.61(br d, J = 7.6 Hz, 2H), 7.52 (br d, J = 7.9 Hz, 2H), 7.46-7.39 (m, 3H),7.35-7.26 (m, 5H), 3.69 (s, 2H), 2.30 (dt, J = 14.8, 7.6 Hz, 2H), 2.22-2.12 (m, 2H), 2.12 -2.03 (m, 2H), 1.57-1.47 (m, 2H), 1.21-1.11 (m, 2H),1.07 (t, J = 7.5 Hz, 6H), 0.73 (t, J = 7.2 Hz, 3H) 2.39, A, 467.3 B 69

1-(2,6- diethylphenyl)- 5-{[3-fluoro- 4-(6-fluoro-2- methylpyridin-3-yl)phenyl] methyl}-6- hydroxy-2-(1- methyl-1H- pyrazol-3- yl)-1,4- 1HNMR (500 MHz, DMSO-d6) Shift 7.80 (br t, J = 8.1 Hz, 1H), 7.57 (br t, J= 7.8 Hz, 1H), 7.51 (br s, 1H), 7.41-7.32 (m, 2H), 7.30- 7.22 (m, 1H),7.18 (br d, J = 7.0 Hz, 2H), 7.11-6.93 (m, 1H), 5.55 (dd, J = 9.0, 2.0Hz, 1H), 3.79 (s, 2H), 3.69 (s, 3H), 2.25 (s, 3H), 2.23-2.12 (m, 4H),0.96 (td, J = 7.4, 2.9 Hz, 6H) 1.80, A, 542.1 A dihydropyrimidin- 4-one70

1-(2,6- diethylphenyl)- 5-{[3- fluoro-4-(3- methylpyridin- 4-yl)phenyl]methyl}-6- hydroxy-2-(1- methyl-1H- pyrazol-3- yl)-1,4- 1H NMR (500 MHz,DMSO-d6) Shift 8.63 (br s, 1H), 7.65-7.55 (m, 1H), 7.52 (d, J = 1.8 Hz,1H), 7.42- 7.29 (m, 2H), 7.19 (br d, J = 7.6 Hz, 5H), 5.56 (s, 1H), 3.81(s, 2H), 3.69 (s, 3H), 2.30- 2.11 (m, 7H), 0.96 (t, J = 7.6 Hz, 6H)1.59, A, 524.0 A dihydropyrimidin- 4-one 71

1-(2,6- diethylphenyl)- 5-{[3-fluoro- 4-(2-fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-2-(1- methyl-1H- pyrazol-3-yl)-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 8.10 (br d, J = 4.8Hz, 1H), 7.50 (br s, 1H), 7.36 (s, 1H), 7.31-7.25 (m, 2H), 7.23-7.11 (m,4H), 5.53 (s, 1H), 3.82-3.73 (m, 2H), 3.17 (s, 3H), 2.28-2.10 (m, 4H),2.04 (s, 3H), 0.94 (br t, J = 7.4 Hz, 6H) 1.83, A, 542.1 A 4-one 72

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (6-fluoro-2- methylpyridin-3-yl)phenyl] methyl}-6- hydroxy-2-(2- methyl-1,3- thiazol-4-yl)-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 7.80 (br t, J = 8.2Hz, 1H), 7.52 (s, 1H), 7.36-7.23 (m, 2H), 7.22-7.01 (m, 5H), 3.79 (s,2H), 2.39 (s, 3H), 2.25 (s, 7H), 0.99 (br t, J = 7.4 Hz, 6H) 1.90, A,559.1 A 4-one 73

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (2-fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-2-(4- methyl-1,3- thiazol-2-yl)-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 8.11 (br d, J = 4.9Hz, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 7.29 (br d, J = 7.9 Hz, 1H),7.25-7.06 (m, 5H), 3.82 (s, 2H), 2.33-2.13 (m, 4H), 2.08-2.05 (m, 3H),2.05 (br s, 3H), 0.94 (br t, J = 7.5 Hz, 6H) 1.93, A, 559.3 A 4-one 74

1-(2,6- diethylphenyl)-5- {[3-fluoro-4-(3- methylpyridin-4- yl)phenyl]methyl}-6- hydroxy-2-(2- methyl-1,3- thiazol-4-yl)-1,4-dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.75-8.44 (m,1H), 7.53 (s, 1H), 7.43 (br d, J = 4.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.25(s, 2H), 7.15-7.08 (m, 2H), 7.04 (s, 1H), 3.82 (s, 2H), 2.40 (s, 3H),2.32 (dt, J = 15.0, 7.5 Hz, 2H), 2.27-2.20 (m, 2H), 2.18 (s, 3H), 1.00(br t, J = 7.6 Hz, 6H) 1.74, A, 541.1 A 75

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (3-methylpyridin- 4-yl)phenyl]methyl}-6- hydroxy-2-(4- methyl-1,3- thiazol-2-yl)-1,4-dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.58-8.49 (m,1H), 8.45 (br d, J = 4.6 Hz, 1H), 7.44 (s, 1H), 7.39- 7.31 (m, 1H), 7.25(br d, J = 7.6 Hz, 1H), 7.22 (br s, 2H), 7.19-7.14 (m, 3H), 3.81 (s,2H), 2.22 (dquin, J = 14.9, 7.4 Hz, 4H), 2.12 (s, 3H), 2.06 (s, 3H),0.94 (t, J = 7.5 Hz, 6H) 1.62, A, 541.2 A 76

1-(2,6- diethylphenyl)- 2-(1-ethyl-1H- pyrazol-3-yl)-5- {[3-fluoro-4-(3-methylpyridin-4- yl)phenyl] methyl}-6- hydroxy-1,4- dihydropyrimidin-4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.52 (br s, 1H), 8.45 (br d, J =4.0 Hz, 1H), 7.58 (br s, 1H), 7.38- 7.30 (m, 1H), 7.29-7.19 (m, 3H),7.16 (br d, J = 7.6 Hz, 3H), 5.90 (br s, 1H), 3.94 (q, J = 7.1 Hz, 2H),3.79 (s, 2H), 2.31-2.17 (m, 4H), 2.13 (s, 3H), 1.11 (br t, J = 7.2 Hz,3H), 0.95 (br t, J = 1.61, A, 538.3 A 7.5 Hz, 6H) 77

1-(2,6- diethylphenyl)- 2-(1-ethyl-1H- pyrazol-3-yl)-5- {[3-fluoro-4-(2-fluoro-3- methylpyridin- 4-yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 8.11 (br d, J = 4.9Hz, 1H), 7.57 (br s, 1H), 7.31 (dt, J = 15.8, 7.8 Hz, 2H), 7.26-7.09 (m,5H), 5.91 (s, 1H), 3.93 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 2.36-2.14 (m,4H), 2.05 (s, 3H), 1.10 (br t, J = 7.2 Hz, 3H), 0.95 (br t, J = 7.5 Hz,6H) 1.98, A, 556.1 A 4-one 78

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (2-fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-2-(2- methyl-1,3- thiazol-4-yl)-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 8.10 (br d, J = 4.6Hz, 1H), 7.51 (s, 1H), 7.34- 7.25 (m, 2H), 7.24-7.15 (m, 3H), 7.13-7.05(m, 2H), 3.89 (s, 2H), 2.38 (s, 3H), 2.30 (dt, J = 14.7, 7.2 Hz, 2H),2.24-2.13 (m, 2H), 2.04 (s, 3H), 0.98 (br t, J = 7.4 Hz, 6H) 1.93, A,559.1 A 4-one 79

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (6-fluoro-2- methylpyridin-3-yl)phenyl] methyl}-6- hydroxy-2-(4- methyl-1,3- thiazol-2-yl)-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 7.79 (br t, J = 8.0Hz, 1H), 7.42 (br s, 1H), 7.38-7.31 (m, 1H), 7.30-7.23 (m, 1H),7.22-7.11 (m, 4H), 7.10- 7.03 (m, 1H), 3.79 (br s, 2H), 2.24 (s, 3H),2.22-2.12 (m, 4H), 2.05 (s, 3H), 0.93 (br t, J = 7.4 Hz, 6H) 1.81, A,559.3 A 4-one 80

1-(2,6- diethylphenyl)- 2-(1-ethyl-1H- pyrazol-3-yl)-5- {[3-fluoro-4-(6-fluoro-2- methylpyridin- 3-yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 7.80 (br t, J = 8.1Hz, 1H), 7.58 (br s, 1H), 7.32 (br d, J = 7.6 Hz, 1H), 7.31- 7.24 (m,1H), 7.23-7.12 (m, 4H), 7.08 (br dd, J = 8.1, 2.3 Hz, 1H), 5.90 (s, 1H),3.94 (q, J = 7.0 Hz, 2H), 3.79 (s, 1H), 2.29-2.25 (m, 3H), 2.24- 1.82,A, 556.3 A 4-one 2.16 (m, 4H), 1.10 (br t, J = 7.2 Hz, 3H), 0.95 (br t,J = 7.5 Hz, 7H) 81

4′-{[1-(2,6- diethylphenyl)- 2-(1-ethyl-1H- pyrazol-3-yl)-6- hydroxy-4-oxo-1,4- dihydropyrimidin- 5-yl]methyl}-2′, 5-difluoro-[1,1′-biphenyl]-2- carboxamide 1H NMR (500 MHz, DMSO-d6) Shift 7.70 (brs, 1H), 7.64-7.45 (m, 2H), 7.35 (br d, J = 7.3 Hz, 3H), 7.17 (br d, J =7.6 Hz, 2H), 7.12-6.96 (m, 2H), 5.91 (br s, 1H), 3.93 (q, J = 7.1 Hz,2H), 3.75 (br s, 2H), 2.23 (q, J = 7.2 Hz, 4H), 1.10 (br t, J = 7.5 Hz,6H) 1.56, A, 584.2 A 82

4′-{[1-(2,6- diethylphenyl)- 6-hydroxy-2- (4-methyl-1,3-thiazol-2-yl)-4- oxo-1,4- dihydropyrimidin- 5-yl]methyl}-2′,4-difluoro-[1,1′- biphenyl]-2- carboxamide 1H NMR (500 MHz, DMSO-d6) Shift7.76-7.66 (m, 1H), 7.42 (s, 1H), 7.34 (br d, J = 5.5 Hz, 2H), 7.27 (brs, 1H), 7.22 (br t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.09 (brd, J = 7.9 Hz, 1H), 7.01 (br d, J = 11.3 Hz, 1H), 3.76 (s, 2H), 2.22 (q,J = 7.3 Hz, 4H), 2.06 (s, 3H), 0.96 (t, J = 7.5 Hz, 6H) 1.73, A, 587.2 A83

1-(2,6- diethylphenyl)-5- {[3-fluoro-4-(1- methyl-2-oxo-1,2-dihydropyridin-3- yl)phenyl]methyl}- 6-hydroxy-2-(4- methyl-1,3-thiazol-2-yl)-1,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6)Shift 7.75 (br d, J = 6.1 Hz, 1H), 7.51-7.39 (m, 2H), 7.39-7.26 (m, 2H),7.16 (br d, J = 7.3 Hz, 2H), 7.10 (br d, J = 7.9 Hz, 1H), 7.05 (br d, J= 11.6 Hz, 1H), 6.29 (br t, J = 6.6 Hz, 1H), 3.76 (br s, 2H), 3.49 (s,3H), 2.23 (q, J = 7.1 Hz, 4H), 2.06 (s, 3H), 0.97 (br t, J = 7.3 Hz,1.73, A, 587.2 A 6H) 84

4′-{[1-(2,6- diethylphenyl)- 6-hydroxy-4- oxo-2-[1- (propan-2-yl)-1H-pyrazol- 3-yl]-1,4- dihydropyrimidin- 5-yl]methyl}-2′, 4-difluoro-[1,1′-biphenyl]-2- 1H NMR (500 MHz, DMSO-d6) Shift 7.58 (s, 1H), 7.35(br d, J = 4.3 Hz, 2H), 7.31-7.25 (m, 2H), 7.23-7.16 (m, 1H), 7.15-7.06(m, 3H), 7.02 (br d, J = 11.3 Hz, 1H), 6.22 (s, 1H), 4.28 (dt, J = 13.0,6.4 Hz, 1H), 3.73 (s, 2H), 2.25 (q, J = 7.3 Hz, 4H), 1.09 (d, J = 6.4Hz, 6H), 0.97 (t, J = 7.5 Hz, 6H) 1.74, A, 598.1 A carboxamide 85

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (2-fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-2-[1- (propan-2-yl)-1H- pyrazol-3-yl]-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 8.10 (br d, J = 4.9Hz, 1H), 7.59 (br s, 1H), 7.34-7.25 (m, 2H), 7.25-7.16 (m, 3H), 7.13 (brd, J = 7.6 Hz, 2H), 6.22 (br s, 1H), 4.28 (dt, J = 13.0, 6.4 Hz, 1H),3.79 (s, 2H), 2.22 (q, J = 7.0 Hz, 4H), 2.05 (s, 3H), 1.09 (br d, J =6.4 Hz, 6H), 0.93 (br t, J = 7.3 Hz, 6H) 2.11, A, 570.2 A 4-one 86

1-(2,6- diethylphenyl)- 5-{[2-fluoro-4- (2-fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-2-(1- methyl-1H- pyrazol-3-yl)-1,4-dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift 8.09 (br d, J = 4.9Hz, 1H), 7.53 (s, 1H), 7.42-7.34 (m, 1H), 7.32-7.21 (m, 2H), 7.22-7.11(m, 4H), 5.54 (s, 1H), 3.79 (s, 2H), 3.70 (s, 3H), 2.32-2.19 (m, 4H),2.16 (s, 3H), 0.96 (t, J = 7.5 Hz, 6H) 1.78, A 542.0 A 4-one 87

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (1-methyl-2- oxo-1,2-dihydropyridin- 3-yl)phenyl] methyl}-6- hydroxy-2-[1- (propan-2-yl)-1H-pyrazol-3-yl]-1,4- 1H NMR (500 MHz, DMSO-d6) Shift 7.74 (br d, J = 6.7Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.45 (br d, J = 6.1 Hz, 1H),7.36-7.25 (m, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.11-7.06 (m, 1H), 7.04 (brd, J = 11.3 Hz, 1H), 6.29 (t, J = 6.9 Hz, 1H), 6.23 (d, J = 1.8 Hz, 1H),4.29 (dt, J = 13.1, 6.6 Hz, 1H), 3.74 (s, 2H), 3.48 (s, 3H), 2.24 (q,1.66 A , 568.1 A dihydropyrimidin- J = 7.4 Hz, 4H), 1.10 (d, J = 4-one6.7 Hz, 6H), 0.96 (t, J = 7.6 Hz, 6H) 88

1-(2,6- diethylphenyl)-5- {[2-fluoro-4-(1- methyl-2-oxo-1,2-dihydropyridin-3- yl)phenyl]methyl}- 6-hydroxy-2-(1- methyl-1H-pyrazol-3-yl)-1,4- dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6)Shift 7.74 (br d, J = 6.4 Hz, 1H), 7.66 (br d, J = 6.7 Hz, 1H),7.60-7.53 (m, 1H), 7.50 (s, 1H), 7.43-7.37 (m, 1H), 7.36-7.27 (m, 1H),7.16 (br d, J = 7.3 Hz, 3H), 6.32 (t, J = 6.9 Hz, 1H), 5.58 (s, 1H),3.73 (s, 2H), 3.68 (s, 3H), 3.50 (s, 3H), 2.26 (q, J = 7.3 Hz, 4H), 0.99(t, J = 7.6 Hz, 6H) 1.35, A, 540.2 A 89

4′-{[1-(2,6- diethylphenyl)- 6-hydroxy-2-(1- methyl-1H-pyrazol-3-yl)-4-oxo-1,4- dihydropyrimidin-5- yl]methyl}-3′,4- difluoro-[1,1′-biphenyl]-2- carboxamide 1H NMR (500 MHz, DMSO-d6) Shift 7.77 (br s,1H), 7.52 (s, 1H), 7.46- 7.39 (m, 2H), 7.39-7.34 (m, 1H), 7.34- 7.28 (m1H), 7.25 (br d, J = 7.9 Hz, 1H, 7.22-7.06 (m, 5H), 5.56 (s, 1H), 3.90(s, 2H), 3.70 (s, 3H), 2.24 (q, J = 7.5 Hz, 4H), 0.99 (br t, J = 7.5 Hz,6H) 1.57, A, 570.1 A 90

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4-(1- methyl-2-oxo-1,2-dihydropyridin-3- yl)phenyl]methyl}- 6-hydroxy-2-[1-(2- methylpropyl)-1H-pyrazol- 3-yl]-1,4- dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift7.73 (br d, J = 6.1 Hz, 1H), 7.55 (br s, 1H), 7.44 (br d, J = 6.4 Hz,1H), 7.37-7.22 (m, 2H), 7.13 (br d, J = 7.0 Hz, 2H), 7.10-6.97 (m, 2H),6.29 (br t, J = 6.7 Hz, 1H), 6.02 (br s, 1H), 3.74 (br s, 2H), 3.69 (brd, J = 6.7 Hz, 2H), 3.44 (br s, 3H), 2.23 (br d, J = 6.7 Hz, 4H), 1.79(br d, J = 5.2 Hz, 1H), 0.97 (br t, J = 1.78, A, 582.0 C 4-one 7.2 Hz,6H), 0.59 (br d, J = 6.1 Hz, 6H) 91

1-(2,6- diethylphenyl)- 5-{[3-fluoro-4- (2-fluoro-3- methylpyridin-4-yl)phenyl] methyl}-6- hydroxy-2-[1-(2- methylpropyl)- 1H-pyrazol-3-yl]-1,4- 1H NMR (500 MHz, DMSO-d6) Shift 8.08 (br d, J = 5.0 Hz, 1H),7.52 (s, 1H), 7.37- 7.24 (m, 2H), 7.21 (br d, J = 7.9 Hz, 2H), 7.18-7.06(m, 3H), 5.97 (s, 1H), 3.76 (br s, 4H), 2.29-2.11 (m, 4H), 2.03 (br s,3H), 1.86-1.71 (m, 1H), 0.93 (bt t, J = 7.4 Hz, 6H), 0.57 (br d, 6.5 Hz,6H) 2.14, A, 584.1 C dihydropyrimidin- 4-one 92

4′-{[1-(2,6- diethylphenyl)- 6-hydroxy-2-[1- (2-methylpropyl)-1H-pyrazol- 3-yl]-4-oxo-1,4- dihydropyrimidin- 5-yl]methyl}-2′,4-difluoro-[1,1′- biphenyl]-2- carboxamide 1H NMR (500 MHz, DMSO-d6)Shift 7.73 (br s, 1H), 7.56 (s, 1H), 7.42-7.27 (m, 3H), 7.21 (br t, J =7.8 Hz, 1H), 7.13 (br d, J = 7.5 Hz, 2H), 7.11- 7.05 (m, 1H), 7.00 (brd, J = 11.4 Hz, 1H), 6.01 (s, 1H), 3.89 (s, 2H), 3.69 (br d, J = 7.2 Hz,2H), 2.31-2.16 (m, 4H), 1.85- 1.72 (m, 1H), 0.98 (br t, J = 7.4 Hz, 6H),0.59 (br d, J = 6.5 Hz, 6H) 1.86, A, 612.0 B 93

2-(1-cyclopropyl- 1H-pyrazol-3-yl)- 1-(2,6- diethylphenyl)-5-{[3-fluoro-4-(1- methyl-2-oxo-1,2- dihydropyridin-3-yl)phenyl]methyl}- 6-hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR (500MHz, DMSO-d6) Shift 7.70 (br d, J = 6.7 Hz, 1H), 7.67 (d, J = 1.8 Hz,1H), 7.44 (br d, J = 6.7 Hz, 1H), 7.36-7.24 (m, 2H), 7.14 (br d, J = 7.6Hz, 2H), 7.07 (br d, J = 7.9 Hz, 1H), 7.01 (br d, J = 11.6 Hz, 1H), 6.30(t, J = 6.9 Hz, 1H), 6.21 (s, 1H), 3.72 (s, 2H), 3.62 (br d, J = 9.5 Hz,1H), 3.47 (s, 3H), 2.19 (q, J = 1.62, A, 566.0 A 7.3 Hz, 4H), 0.94 (t, J= 7.6 Hz, 6H), 0.80-0.70 (m, 2H), 0.59 (br s, 2H) 94

4′-{[2-(1- cyclopropyl- 1H-pyrazol-3-yl)-1- (2,6-diethylphenyl)-6-hydroxy- 4-oxo-1,4- dihydropyrimidin- 5-yl]methyl}-2′,4-difluoro-[1,1′- biphenyl]-2- carboxamide 1H NMR (500 MHz, DMSO-d6) Shift7.72 (br s, 1H), 7.68 (s, 1H), 7.42-7.26 (m, 3H), 7.19 (s, 1H), 7.14 (brd, J = 7.6 Hz, 2H), 7.07 (br d, J = 7.7 Hz, 1H), 6.99 (br d, J = 11.7Hz, 1H), 6.21 (br s, 1H), 3.68-3.48 (m, 3H), 2.20 (q, J = 7.3 Hz, 4H),0.94 (br t, J = 7.5 Hz, 6H), 0.75 (br d, J = 6.3 Hz, 2H), 0.59 (br s,2H) 1.72, A, 596.2 A

Example 95(S)-3-(1-(2-butyl-5-(4-(6-fluoro-2-methylpyridin-3-yl)benzyl)-6-hydroxy-4-oxopyrimidin-1(4H)-yl)propyl)benzonitrile

Compound 95a. ethyl pentanimidate hydrochloride

To a solution of pentanenitrile (7.11 g, 86.1 mmol) in ethanol (60 ml)at 0° C. was added acetyl chloride (30.4 mL, 428 mmol) dropwise. Thecooling bath was removed and the reaction mixture was stirred overnightat RT. The reaction solvent was removed under vacuum and the residue wastriturated with Et₂O. The resultant slurry was filtered and the filtercake was washed with Et₂O and dried under vacuum to give Compound 95a(8.21 g, 58% yield) as a white solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ12.36 (br s, 1H), 11.47 (br s, 1H), 4.64 (q, J=7.2 Hz, 2H), 2.74 (t,J=7.7 Hz, 2H), 1.76-1.66 (m, 2H), 1.49 (t, J=7.0 Hz, 3H), 1.45-1.37 (m,2H), 0.95 (t, J=7.4 Hz, 3H).

Compound 95b. 3-propionylbenzonitrile

To a solution of 1-(3-bromophenyl)propan-1-one (950 mg, 4.46 mmol) inDMF (10 ml) was added copper(I) cyanide (998 mg, 11.2 mmol). Thereaction vessel was sealed and the reaction mixture was stirred at 165°C. overnight. The reaction mixture was quenched by the addition of 30%NH₄OH and extracted with EtOAc (2×). The EtOAc layers were combined andthe composite was washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 60% EtOAc in hexane to giveCompound 95b (400 mg, 56% yield) as an off-white solid. MS m/z=160.0(M+H). ¹H NMR (CHLOROFORM-d) δ: 8.26 (s, 1H), 8.21 (dt, J=7.9, 1.4 Hz,1H), 7.86 (dt, J=7.7, 1.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 3.04 (q,J=7.2 Hz, 2H), 1.58-1.61 (m, 1H), 1.28 (t, J=7.3 Hz, 3H).

Compound 95c.(S)-N-((S)-1-(3-cyanophenyl)propyl)-2-methylpropane-2-sulfamide

To a solution of Compound 95b (400 mg, 2.51 mmol) in THF (10 ml) wasadded titanium(IV) ethoxide (1.15 g, 5.03 mmol) and(S)-2-methylpropane-2-sulfinamide (335 mg, 2.76 mmol). The reactionmixture was stirred at 75° C. for 4 hrs. The reaction mixture was cooledto −48° C. and was added dropwise to a −48° C. solution of sodiumborohydride (380 mg, 10.1 mmol) in THF (4 mL). The reaction mixture wasallowed to warm to RT over 3 hrs and was then carefully quenched by theaddition of MeOH. With rapid stirring, the reaction mixture was pouredinto an equal volume of brine, the resulting suspension was filteredthrough celite and the celite cake was washed with EtOAc. The two-phasefiltrate was split and the organic phase was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 100% EtOAc in hexane to giveCompound 95c (450 mg, 68% yield) as a white solid. MS m/z=265.1 (M+H).¹H NMR (CHLOROFORM-d) δ: 7.57-7.65 (m, 2H), 7.46-7.52 (m, 1H), 7.22-7.33(m, 1H), 4.31-4.39 (m, 1H), 3.32-3.54 (m, 1H), 1.74-2.12 (m, 2H), 1.26(s, 9H), 0.85 (t, J=7.3 Hz, 3H).

Compound 95d. (S)-3-(1-aminopropyl)benzonitrile

To a solution of Compound 95c (450 mg, 1.70 mmol) in MeOH (5 ml) wasadded 4N HCl in dioxane (0.85 mL, 3.4 mmol), and the reaction mixturewas stirred at RT for 1 hr. The reaction mixture was concentrated underreduced pressure to give Compound 95d (335 mg, 100% yield) as a whitesolid. MS m/z=161.0 (M+H). ¹H NMR (METHANOL-d4) δ: 7.82-7.88 (m, 2H),7.77-7.81 (m, 1H), 7.67-7.73 (m, 1H), 4.20-4.34 (m, 1H), 1.95-2.13 (m,2H), 0.93 (t, J=7.4 Hz, 3H).

Compound 95e. (S)-N-(1-(3-cyanophenyl)propyl)pentanimidamide

To a solution of Compound 95d (1.61 g, 8.19 mmol) in MeOH (20 ml) wasadded Compound 95a (2.44 g, 14.2 mmol), and DIEA (4.23 g, 32.7 mmol) thereaction mixture was stirred at RT for 14 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified viapreparative HPLC with the following conditions: Column: Phen Luna AXIAC18, 30×100 mm, 5-μm particles; Mobile Phase A: 10:90 MeOH: water with0.1% TFA; Mobile Phase B: 90:10 MeOH: water with 0.1% TFA; Gradient:0-100% B over 10 minutes, then a 2-minute hold at 100% B; Flow: 40mL/min. Fractions containing the 95e were combined, concentrated underreduced pressure and the residue was partitioned between DCM and 1NNaOH. Compound 95e was extracted with DCM (2×), the organic phases werecombined and the composite was dried over MgSO₄ and concentrate underreduced pressure to give a white solid (1.4 g, 70% yield). MS m/z=244.2(M+H). ¹H NMR (CHLOROFORM-d) δ: 7.61-7.63 (m, 1H), 7.56-7.60 (m, 1H),7.51-7.56 (m, 1H), 7.40-7.47 (m, 1H), 5.32 (s, 1H), 2.24 (t, J=7.8 Hz,2H), 1.66-1.86 (m, 2H), 1.54-1.62 (m, 2H), 1.23-1.44 (m, 2H), 0.87-0.97(m, 6H), 0.01-0.03 (m, 1H).

Compound 95f. diethyl 2-(4-bromobenzyl)malonate3-propionylbenzonitrile

To a slurry of 60% NaH (699 mg, 17.5 mmol) in THF (20 ml) was addeddiethyl malonate (2.0 g, 13 mmol) dropwise and the reaction mixture wasstirred at RT for 1 hr. The reaction mixture cooled to 0° C. and asolution of 1-bromo-4-(bromomethyl)benzene (3.13 g, 12.5 mmol) in THF (5mL) was added dropwise. The reaction mixture was allowed to warm andstir for 14 h at RT. The reaction mixture was quenched by the additionof EtOH, filtered through celite and the celite cake was washed withEtOAc. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel chromatography eluting with 0 to 70%EtOAc in hexane to give Compound 95f (1.35 g, 33% yield) as a colorlessoil. MS m/z=329.0 (M+H). ¹H NMR (CHLOROFORM-d) δ: 7.38-7.52 (m, 2H),7.07-7.20 (m, 2H), 4.09-4.37 (m, 4H), 3.59 (t, J=7.8 Hz, 1H), 3.16 (d,J=7.9 Hz, 2H), 1.56 (s, 1H), 1.22 (t, J=7.2 Hz, 6H), −0.01-0.05 (m, 1H).

Compound 95g. 2-(4-bromobenzyl)malonic acid

To a solution of Compound 95f (500 mg, 1.52 mmol) in a mixture of EtOH(2.5 ml) and water (1.25 mL) was added KOH (298 mg, 5.32 mmol) and thereaction mixture was stirred at RT for 14 h. The reaction mixture wasacidified with 3N HCl and the product was extracted with Et₂O (3×). Theorganic phases were combined and the composite was dried over MgSO₄ andconcentrated under reduced pressure to give Compound 395g (420 mg, 100%yield) as a white solid. MS m/z=272.9 (M+H). ¹H NMR (CHLOROFORM-d) δ:7.42-7.47 (m, 2H), 7.07-7.16 (m, 2H), 3.76 (t, J=7.4 Hz, 1H), 3.28 (d,J=7.4 Hz, 2H).

Compound 95h. 2-(4-bromobenzyl)malonyl dichloride

To a solution of Compound 95g (802 mg, 2.94 mmol) in DCM (25 ml) wasadded 2M oxalyl chloride in DCM (2.94 mL, 5.87 mmol) and DMF (3 drops).The reaction mixture was stirred at RT for 1 hr. The reaction mixturewas used without further purification in the next reaction step.

Compound 95i.(S)-3-(1-(5-(4-bromobenzyl)-2-butyl-6-hydroxy-4-oxopyrimidin-1(4H)-yl)propyl)benzonitrile

To Compound 95h (911 mg, 2.94 mmol) was added a solution of Compound 38e(550 mg, 2.26 mmol) in DCM (8 mL) and TEA (915 mg, 904 mmol) and thereaction mixture was stirred at RT for 2 hrs. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography eluting with 0 to 60% EtOAc in hexane to giveCompound 95i (501 mg, 46% yield) as a pale yellow solid. MS m/z=480.2(M+H). ¹H NMR (CHLOROFORM-d) δ: 7.62 (br s, 1H), 7.52-7.59 (m, 2H),7.43-7.52 (m, 2H), 7.30-7.39 (m, 2H), 4.84-4.96 (m, 1H), 3.73 (br s,2H), 2.21-2.35 (m, 2H), 1.77-1.87 (m, 2H), 1.57-1.70 (m, 2H), 1.41-1.49(m, 2H), 1.02 (t, J=6.9 Hz, 3H), 0.91-0.97 (m, 3H). Human APJ cAMP EC₅₀potency range: B.

Example 95.(S)-3-(1-(2-butyl-5-(4-(6-fluoro-2-methylpyridin-3-yl)benzyl)-6-hydroxy-4-oxopyrimidin-1(4H)-yl)propyl)benzonitrile

To a 5 mL microwave vial were added Compound 95i (30.1 mg, 0.0620 mmol),(6-fluoro-2-methylpyridin-3-yl)boronic acid (29.1 mg, 0.187 mmol),Pd(dppf)Cl₂CH₂Cl₂ (5 mg, 0.006 mmol), 1.5 M Na₂CO₃ (0.125 mL, 0.187mmol), and THE (1 mL). The reaction mixture was degassed with argon andstirred at 110° C. under microwave irradiation for 1 hr. The reactionmixture was filtered and concentrated under reduced pressure. Theresidue was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile: water with 10 mM ammonium acetate; Gradient: 30-70% Bover 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.Fractions containing Compound 95 were combined and dried via centrifugalevaporation (13.9 mg, 43% yield) a white solid. The estimated purity byLCMS analysis was 99.2%, HPLC method B, RT=2.03 min, MS m/z=511.2 (M+H).¹H NMR (DMSO-d6) 5:7.70-7.80 (m, 2H), 7.62-7.70 (m, 1H), 7.49-7.62 (m,2H), 7.14-7.35 (m, 4H), 6.98-7.08 (m, 1H), 5.23-5.59 (m, 1H), 3.38 (brs, 2H), 2.77-2.96 (m, 2H), 2.28-2.48 (m, 5H), 1.57-1.72 (m, 2H),1.31-1.47 (m, 2H), 0.79-1.01 (m, 6H). Human APJ cAMP EC₅₀ potency range:A.

Examples 96 to 136 were prepared as described in the general proceduregiven for Example 95.

APJ Rt(min) cAMP method Potency Ex# Structure Name NMR M + H range  96

3-[(1S)-1-(2-butyl-6- hydroxy-5-{[4-(2- methylpyridin-3-yl)phenyl]methyl}-4- oxo-1,4- dihydropyrimidin-1- yl)propyl]benzonitrile 1H NMR (DMSO-d6) Shift: 8.42 (br s, 1H), 7.63-7.77 (m, 2H),7.55 (br s, 2H), 7.24-7.39 (m, 3H), 7.17-7.24 (m, 3H), 5.36-5.47 (m,1H), 3.81-3.98 (m, 2H), 2.76-2.93 (m, 2H), 2.53-2.56 (m, 5H), 2.33-2.47(m, 5H), 1.53-1.71 (m, 2H), 1.28-1.50 (m, 2H), 0.85 (s, 6H) 1.77, A,493.01 A  97

3-[(1S)-1-(2- butyl-5-{[4-(6- fluoropyridin-3-yl) phenyl]methyl}-6-hydroxy-4-oxo-1,4- dihydropyrimidin- 1-yl)propyl] benzonitrile 1H NMR(DMSO-d6) Shift: 8.48 (br s, 1H), 8.17-8.26 (m, 1H), 7.69-7.77 (m, 1H),7.67 (br s, 1H), 7.51-7.62 (m, 3H), 7.16-7.31 (m, 4H), 5.30-5.57 (m,1H), 3.80- 3.96 (m, 2H), 2.79-2.93 (m, 2H), 2.05-2.20 (m, 2H), 1.58-1.71(m, 2H), 1.34-1.43 (m, 2H), 0.80- 0.93 (m, 6H) 1.91, A, 497.0 A  98

3-[(1S)-1-(2-butyl-6- hydroxy-5-{[4-(3- methylpyridin-4-yl)phenyl]methyl}- 4-oxo-1,4- dihydropyrimidin-1- yl)propyl]benzonitrile 1H NMR (DMSO- d6) Shift: 8.47 (s, 1H), 8.36-8.41 (m, 1H),7.62-7.75 (m, 2H), 7.48-7.60 (m, 2H), 7.13-7.30 (m, 5H), 5.18-5.66 (m,1H), 3.44-3.66 (m, 2H), 2.74-2.92 (m, 2H), 2.16-2.28 (m, 5H), 1.56-1.72(m, 2H), 1.28-1.46 (m, 2H), 0.76-0.95 (m, 6H) 1.78, A, 493.2 A  99

3-[(1S)-1-(2- butyl-5-{[4- (2-fluoro-3- methylpyridin-4-yl)phenyl]methyl}-6- hydroxy-4-oxo-1,4- dihydropyrimidin-1- yl)propyl]benzonitrile 1H NMR (DMSO- d6) Shift: 7.93-8.19 (m, 1H), 7.63-7.78 (m,2H), 7.47-7.62 (m, 2H), 7.14-7.32 (m, 5H), 5.27-5.59 (m, 1H), 3.36-3.52(m, 2H), 2.76-2.97 (m, 2H), 2.10-2.21 (m, 5H), 1.54-1.74 (m, 2H),1.29-1.46 (m, 2H), 0.73-0.96 (m, 6H) 1.98, A, 511.3 A 100

3-[(1S)-1-(2- butyl-5-{[4- (5-chloro-2-oxo-1,2- dihydropyridin-1-yl)phenyl]methyl}-6- hydroxy-4-oxo-1-4- dihydropyrimidin-1- yl)propyl]benzonitrile 1H NMR (DMSO- d6) Shift: 7.81-7.90 (m, 1H), 7.62-7.75 (m,2H), 7.46-7.60 (m, 3H), 7.29-7.40 (m, 1H), 7.15-7.28 (m, 3H), 6.43-6.57(m, 1H), 5.28-5.50 (m, 1H) 3.51-3.61 (m, 2H), 2.75-2.94 (m, 2H),1.96-2.21 (m, 2H), 1.56-1.70 (m, 2H), 1.30-1.43 (m, 2H), 0.72-0.97 (m,6H) 1.77, A, 529.2 A 101

3-[(1S)-1-{2- butyl-5-[(4- cyclopropylphenyl) methyl]-6-hydroxy-4-oxo-1,4- dihydropyrimidin-1- yl}propylbenzonitrile 1H NMR (DMSO- d6)Shift: 7.67-7.75 (m, 1H), 7.60-7.66 (m, 1H), 7.48-7.61 (m, 1H),6.78-7.02 (m, 5H), 5.31-5.55 (m, 1H), 3.79-3.96 (m, 2H), 2.75-2.89 (m,2H), 2.33-2.45 (m, 2H), 1.76-1.87 (m, 1H), 1.52-1.71 (m, 2H), 1.28-1.43(m, 2H), 0.87 (br d, J = 6.5 Hz, 4H), 0.79-0.85 (m, 6H) 2.04 min, A,442.3 A 102

3-[(1S)-1-{2- butyl-5-[(4- cyclopropylphenyl) methyl]-6-hydroxy-4-oxo-1,4- dihydropyrimidin-1- yl}propyl] benzonitrile 1H NMR (DMSO- d6)Shift: 7.65-7.77 (m, 1H), 7.50-7.62 (m, 1H), 7.12-7.25 (m, 1H),6.96-7.11 (m, 1H), 6.29-6.39 (m, 1H), 6.27-6.40 (m, 1H), 6.20 (br d, J =6.6 Hz, 1H), 5.22- 5.57 (m, 1H), 3.25- 3.38 (m, 2H), 2.73- 2.91 (m, 2H),2.26- 2.42 (m, 2H), 2.03- 2.13 (m, 1H), 1.58- 1.74 (m, 2H), 1.30- 1.44(m, 2H), 0.86- 2.09, A, 442.0 B 0.93 (m, 4H), 0.78- 0.86 (m, 6H) 103

2-butyl-5-{[4- (2-fluoro-3- methylpyridin-4- yl)phenyl]methyl}-1-[(1S)-1-(3- fluorophenyl) propyl]-6- hydroxy-1,4- dihydropyrimidin-4-one 1H NMR (DMSO- d6) Shift: 7.93-8.21 (m, 1H), 7.33-7.44 (m, 2H),7.23-7.33 (m, 3H), 7.16-7.21 (m, 1H), 7.05-7.15 (m, 1H), 6.95-7.06 (m,2H), 5.15-5.52 (m, 1H), 3.41-3.65 (m, 2H), 2.66-3.00 (m, 2H), 2.10-2.22(m, 5H), 1.46-1.76 (m, 2H), 1.25-1.45 2.14, A, 504.0 A (m, 2H),0.77-0.91 (m, 6H) 104

2-butyl-5-{[4- (6-fluoro-2- methylpyridin-3- yl)phenyl]methyl}-1-[(1S)-1-(3- fluorophenyl) propyl]-6- hydroxy-1,4- dihydropyrimidin-4-one 1H NMR (DMSO- d6) Shift: 7.75 (t, J = 7.6 Hz, 2H), 7.33-7.46 (m,2H), 7.15-7.32 (m, 3H), 7.06-7.16 (m, 1H), 6.97-7.06 (m, 2H), 5.20-5.58(m, 1H), 3.38-3.65 (m, 2H), 2.67-2.96 (m, 2H), 2.27-2.45 (m, 5H),1.46-1.73 (m, 2H), 2.10, A, 504.3 A 1.22-1.47 (m, 2H), 0.73-0.97 (m, 6H)105

2-butyl-1-[(1S)-1-(3- fluorophenyl)propyl]- 6-hydroxy-5-{[4-(2-methylpyridin-3-yl) phenyl]methyl}-1,4- dihydropyrimidin- 4-one 1H NMR(DMSO- d6) Shift: 8.28-8.52 (m, 1H), 7.56 (br d, J = 6.7 Hz, 1H),7.15-7.49 (m, 6H), 6.96-7.13 (m, 3H), 5.20-5.60 (m, 1H), 3.45-3.74 (m,2H), 2.71-3.00 (m, 2H), 2.40 (s, 5H), 1.48- 1.76 (m, 2H), 1.21- 1.50 (m,2H), 0.80- 0.89 (m, 6H) 1.94, A, 486.3 A 106

2-butyl-1-[(1S)-1- (3-fluorophenyl) propyl]-6- hydroxy-5-{[4-(3-methylpyridin-4- yl)phenyl] methyl}-1,4- dihydropyrimidin- 4-one 1H NMR(DMSO- d6) Shift: 8.26-8.59 (m, 2H), 7.15-7.47 (m, 6H), 6.96-7.14 (m,3H), 5.26-5.47 (m, 1H), 3.83-3.97 (m, 2H), 2.73-2.93 (m, 2H), 2.18-2.30(m, 5H), 1.49-1.75 (m, 2H), 1.28-1.50 (m, 2H), 0.77-0.92 (m, 6H) 1.93,A, 486.2 A 107

2-(2- cyclopropylethyl)- 1-[(1S)-1-(3,5- difluorophenyl) propyl]-5-{[4-(6-fluoro-2- methylpyridin-3- yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 7.60-7.76 (m, 1H),7.07-7.33 (m, 4H), 6.93-7.05 (m, 2H), 6.75-6.90 (m, 2H), 5.15-5.55 (m,1H), 3.34-3.48 (m, 2H), 2.73-3.03 (m, 2H), 2.29 (s, 5H), 1.39-1.63 (m,2H), 0.78 (t, J = 7.2 Hz, 3H), 0.26-0.45 (m, 2H), 0.10-0.27 2.25, A,534.0 A (m, 1H), −0.10-0.10 (m, 2H) 108

1-[(1S)-1-(3,5- difluorophenyl) propyl]-5-{[4- (2-fluoro-3-methylpyridin-4- yl)phenyl] methyl}-6- hydroxy-2- [(propan-2-yloxy)methyl]-1,4- dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift:8.02-8.11 (m, 1H), 7.22-7.29 (m, 4H), 7.15-7.21 (m, 1H), 7.04-7.12 (m,1H), 6.92-7.05 (m, 2H), 5.19-5.37 (m, 1H), 4.51-4.66 (m, 2H), 4.28-4.47(m, 2H), 3.47-3.68 (m, 1H), 2.32-2.46 (m, 2H), 2.14 (s, 3H), 0.98-1.16(m, 6H), 2.16, A, 538.0 A 0.85 (br t, J = 7.2 Hz, 3H) 109

2-(2- cyclopropylethyl)- 1-[(1S)-1-(3,5- difluorophenyl) propyl]-6-hydroxy-5-{[4-(2- methylpyridin-3-yl) phenyl]methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 8.31-8.43 (m, 1H),7.38-7.55 (m, 1H), 7.07-7.33 (m, 4H), 6.97-7.07 (m, 1H), 6.74-6.91 (m,3H), 5.09-5.49 (m, 1H), 3.10 (s, 2H), 2.73-2.96 (m, 2H), 2.20-2.39 (m,5H), 1.35-1.65 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H), 0.26-0.44 (m, 2.04, A,516.2 A 2H), 0.08-0.26 (m, 1H), −0.10-0.07 (m, 2H) 110

2-(2- cyclopropylethyl)- 1-[(1S)-1-(3,5- difluorophenyl) propyl]-6-hydroxy-5-{[4-(3- methylpyridin-4- yl)phenyl] methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 8.29-8.48 (m, 2H),6.96-7.37 (m, 5H), 6.78-6.91 (m, 3H), 5.21-5.51 (m, 1H), 3.45-3.69 (m,2H), 2.72-2.93 (m, 2H), 2.21-2.41 (m, 2H), 2.13-2.23 (m, 3H), 1.35-1.64(m, 2H), 0.77 (t, J = 7.0 Hz, 3H), 0.27- 0.40 (m, 2H), 0.11- 1.99, A,516.3 A 0.25 (m, 1H), −0.13- 0.08 (m, 2H) 111

1-[(1S)-1-(3,5- difluorophenyl) propyl]-6- hydroxy-5-{[4-(2-methylpyridin-3- yl)phenyl]methyl}- 2-[(propan-2- yloxy)methyl]-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 8.54-8.63 (m, 1H),7.85-7.96 (m, 1H), 7.56 (br t, J = 6.1 Hz, 1H), 7.19-7.32 (m, 4H), 7.16(s, 1H), 7.04- 7.12 (m, 1H), 6.98- 7.04 (m, 1H), 5.25- 5.45 (m, 1H),4.33- 4.74 (m, 2H), 3.63 (s, 2H), 3.38-3.51 (m, 1H), 2.38-2.50 (m, 2.00,A, 520.0 A 5H), 1.02-1.14 (m, 6H), 0.86 (t, J = 7.2 Hz, 3H) 112

1-[(1S)-1-(3,5- difluorophenyl) propyl]- 5-{[4-(6-fluoro-2-methylpyridin-3- yl)phenyl] methyl}-6- hydroxy-2-[(propan-2-yloxy)methyl]-1,4- dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift:7.70-7.78 (m, 1H), 7.18-7.25 (m, 3H), 6.94-7.12 (m, 5H), 5.13-5.46 (m,1H), 4.31-4.64 (m, 2H), 3.52-3.67 (m, 2H), 3.33-3.52 (m, 1H), 2.35-2.46(m, 2H), 2.31-2.36 (m, 3H), 1.01-1.14 (m, 6H), 0.78-0.92 (m, 3H) 2.10,A, 538.0 A 113

2-(2- cyclopropylethyl)- 1-[(1S)-1-(3,5- difluorophenyl) propyl]-5-{[4-(2-fluoro-3- methylpyridin-4- yl)phenyl]methyl}- 6-hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 7.96-8.06 (m, 1H),6.99-7.35 (m, 6H), 6.78-6.93 (m, 2H), 5.15-5.51 (m, 1H), 3.55 (br s,2H), 2.71-2.95 (m, 2H), 2.14-2.41 (m, 2H), 2.03-2.17 (m, 3H), 1.36-1.64(m, 2H), 0.78 (t, J = 7.2 Hz, 3H), 0.09-0.41 (m, 3H), −0.19-0.08 2.20,A, 534.1 A (m, 2H) 114

1-[(1S)-1-(3,5- difluorophenyl) propyl]-6- hydroxy-5-{[4-(3-methylpyridin-4- yl)phenyl]methyl}- 2-[(propan-2- yloxy)methyl]-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 7.20-7.35 (m, 4H),7.10-7.17 (m, 2H), 7.02-7.10 (m, 3H), 6.98-7.02 (m, 1H), 5.21-5.48 (m,1H), 3.89 (s, 2H), 3.17 (s, 2H), 2.77-3.02 (m, 1H), 2.40-2.46 (m, 2H),2.26 (s, 3H), 1.07 (br s, 6H), 0.85 (br t, J = 7.0 Hz, 3H) 2.00, A,520.0 A 115

1-[(1S)-1-(3,5- difluorophenyl)-2- methylpropyl]-6- hydroxy-5-{[4-(2-methylpyridin-3- yl)phenyl]methyl}- 2-[(propan-2- yloxy)methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 8.42 (br d, J = 3.7 Hz,1H), 7.54 (br d, J = 7.6 Hz, 1H), 7.37 (br d, J = 7.9 Hz, 2H), 7.22-7.29(m, 1H), 7.17-7.22 (m, 4H), 7.10-7.17 (m, 1H), 4.92 (br d, J = 10.4 Hz,1H), 4.48- 4.66 (m, 2H), 3.55- 3.63 (m, 2H), 2.38 2.13, A, 534.3 A (s,3H), 1.20 (br d, J = 5.8 Hz, 6H), 1.00 (br d, J = 6.1 Hz, 1H), 0.94 (brd, J = 6.1 Hz, 3H), 0.82 (br d, J = 6.4 Hz, 3H) 116

4′-({1-[(1S)-1-(3,5- difluorophenyl)-2- methylpropyl]-6-hydroxy-4-oxo-2- [(propan-2- yloxy)methyl]-1,4- dihydropyrimidin-5-yl}methyl)-4-fluoro- [1,1′-biphenyl]-2- carboxamide 1H NMR (DMSO- d6)Shift: 7.70 (br s, 1H), 7.32-7.43 (m, 3H), 7.30 (br d, J = 7.7 Hz, 1H),7.22 (br d, J = 7.5 Hz, 2H), 7.06-7.18 3H), 4.91 (br d, J = 10.0 Hz,1H), 4.46-4.69 (m, 2H), 3.74-3.96 (m, 2H), 3.55 (br s, 1H), 1.15-1.24(m, 6H), 2.13, A, 579.9 A 1.00 (br d, J = 6.0 Hz, 1H), 0.94 (br d, J =5.2 Hz, 3H), 0.84 (br d, J = 5.4 Hz, 3H) 117

4′-{[2-(2- cyclopropylethyl)-1- [(1S)-1-(3,5- difluorophenyl)-2-methylpropyl]-6- hydroxy-4-oxo-1,4- dihydropyrimidin-5-yl]methyl}-4-fluoro- [1,1′-biphenyl]-2- carboxamide 1H NMR (DMSO- d6)Shift: 7.66 (br s, 1H), 7.18-7.31 (m, 5H), 7.13 (br d, J = 7.1 Hz, 3H),7.03 (br d, J = 7.0 Hz, 2H), 6.93 (br s, 1H), 4.79 (br d, J = 9.3 Hz,1H), 3.04- 3.15 (m, 2H), 2.80- 3.00 (m, 2H), 1.46- 1.63 (m, 2H), 0.99-1.12 (m, 1H), 0.85 2.05, A, 576.1 A (br d, J = 5.6 Hz, 3H), 0.72 (br d,J = 5.7 Hz, 3H), 0.23-0.38 (m, 2H), 0.07-0.22 (m, 1H), −0.12-0.05 (m,2H) 118

5-{[3-fluoro- 4-(2-fluoro- 3-methylpyridin-4- yl)phenyl]methyl}-6-hydroxy-2-(4-methyl- 1,3-thiazol-2- yl)-1-[(1S)-1- phenylpropyl]-1,4-dihydropyrimidin- 4-one 1H NMR (500 MHz, DMSO-d6) Shift 8.07 (d, J = 4.9Hz, 1H), 7.61 (s, 1H), 7.31-7.14 (m, 6H), 7.07 (br d, J = 7.9 Hz, 1H),7.01 (br d, J = 11.0 Hz, 1H), 6.91 (br t, J = 7.3 Hz, 1H), 3.78-3.55 (m,3H), 2.62-2.44 (m, 2.28, A, 545.1 A 2H), 2.40 (s, 3H), 2.02 (s, 3H),0.84 (br t, J = 7.3 Hz, 3H) 119

5-{[3-fluoro-4-(1- methyl-2-oxo-1,2- dihydropyridin-3- yl)phenyl]methyl}-6- hydroxy-2- (4-methyl- 1,3-thiazol-2- yl)-1-[(1S)-1-phenylpropyl]-1,4- dihydropyrimidin- 1H NMR (500 MHz, DMSO-d6) Shift7.73 (br d, J = 6.7 Hz, 1H), 7.65 (s, 1H), 7.43 (br d, J = 6.1 Hz, 1H),7.33- 7.15 (m, 5H), 6.99- 6.84 (m, 3H), 6.28 (t, J = 6.6 Hz, 1H),3.70-3.54 (m, 1H), 3.47 (s, 3H), 3.43- 1.88, A, 560.2 A 4-one 3.37 (m,2H), 2.63- 2.48 (m, 2H), 2.43 (s, 3H), 0.86 (br t, J = 7.2 Hz, 3H) 120

2′,4-difluoro- 4′-{[6-hydroxy- 2-(4-methyl-1,3- thiazol-2-yl)-4-oxo-1-[(1S)-1- phenylpropyl]-1,4- dihydropyrimidin- 5-yl]methyl}-[1,1′-biphenyl]-2- carboxamide 1H NMR (500 MHz, DMSO-d6) δ 7.68 (br d, J =15.9 Hz, 2H), 7.34 (br d, J = 7.6 Hz, 2H), 7.29 (br s, 3H), 7.22-7.12(m, 2H), 6.95 (br d, J = 7.6 Hz, 2H), 6.88 (br d, J = 11.3 Hz, 1H),2.65- 2.46 (m, 2H), 2.45-2.39 (m, 3H), 0.88 (br t, 2.06, B, 570.9 A 7.2Hz, 3H) 121

3-fluoro-5- [(1S)-1-(6- hydroxy-5-{[4-(2- methylpyridin-3-yl)phenyl]methyl}- 4-oxo-2-[(propan-2- yloxy)methyl]-1,4-dihydropyrimidin- 1-yl)-2-methylpropyl] benzonitrile 1H NMR (DMSO- d6)Shift: 7.92-7.97 (m, 1H), 7.75 (br d, J = 7.3 Hz, 1H), 7.43-7.65 (m,2H), 7.15-7.37 (m, 5H), 7.08 (s, 1H), 4.97 (br d, J = 10.4 Hz, 1H),4.50-4.74 (m, 2H), 3.81-3.94 (m, 1H), 3.54 (br s, 2H), 2.46-2.50 (m,3H), 1.21 (br t, J = 6.1 Hz, 6H), 1.00 (br d, J = 6.1 Hz, 1H), 1.65, B,541.1 B 0.94 (br d, J = 6.1 Hz, 3H), 0.83 (br d, J = 6.1 Hz, 3H) 122

1-[(1R)-1-(3,5- difluorophenyl)-2- methoxyethyl]-2- (ethoxymethyl)-6-hydroxy-5-{[4-(3- methylpyridin-4- yl)phenyl] methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO- d6) Shift: 8.68 (br s, 1H),8.59-8.65 (m, 1H), 7.24-7.37 (m, 4H), 7.06-7.12 (m, 2H), 6.89-6.95 (m,2H), 5.45-5.85 (m, 1H), 4.30-4.36 (m, 2H), 4.03-4.16 (m, 2H), 3.58-3.73(m, 2H), 3.30 (s, 2H), 2.47-2.51 (m, 3H) 2.32 (s, 3H), 1.04 1.98, A,522.0 A (br t, J = 6.9 Hz, 3H) 123

1-[(1R)-1-(3,5- difluorophenyl)-2- methoxyethyl]-2- (ethoxymethyl)-6-hydroxy-5-{[4-(2- methylpyridin-3- yl)phenyl] methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 8.57-8.67 (m, 1H),7.89-8.02 (m, 1H), 7.52-7.69 (m, 1H), 7.22-7.32 (m, 4H), 7.10-7.15 (m,1H), 6.94 (br d, J = 7.4 Hz, 2H), 5.60 (br s, 1H), 4.37-4.70 (m, 2H),4.07-4.36 (m, 2H), 3.61 (br s, 2H), 3.54 (br s, 2H), 3.31 (s, 3H),2.44-2.51 1.57, A, 522.1 A (m, 3H), 1.05 (br t, J = 6.6 Hz, 3H) 124

1-[(1R)-1-(3,5- difluorophenyl)-2- methoxyethyl]-2- (ethoxymethyl)-5-{[4-(6-fluoro-2- methylpyridin- 3-yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 7.73 (br t, J = 8.2 Hz,1H), 7.20 (s, 4H), 7.06-7.16 (m, 1H), 7.02 (br d, J = 6.1 Hz, 1H), 6.92(br d, J = 7.3 Hz, 2H), 5.59 (br s, 1H), 4.36-4.68 (m, 2H), 4.02-4.35(m, 2H), 3.44-3.55 (m, 2H), 3.30 (s, 2H), 2.33 (s, 3H), 1.04 (t, 2.16,A, 540.2 A J = 6.9 Hz, 3H) 125

1-[(1R)-1-(3,5- difluorophenyl)-2- methoxyethyl]-2- (ethoxymethyl)-5-{[4-(6- fluoropyridin-3- yl)phenyl]methyl}- 6-hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 8.44 (br s, 1H), 8.19(t, J = 8.1 Hz, 1H), 7.51 (br d, J = 7.9 Hz, 2H), 7.22 (br d, J = 7.9Hz, 3H), 7.08 (br t, J = 9.0 Hz, 1H), 6.90 (br d, J = 7.6 Hz, 2H), 5.58(br s, 1H), 4.29- 4.39 (m, 2H), 3.65-3.72 (m, 4H), 3.52-3.60 (m, 2H),3.30 (s, 3H), 1.03 (br t, J = 6.9 Hz, 3H) 1.71, A, 526.2 B 126

1-[(1R)-1-(3,5- difluorophenyl)-2- methoxyethyl]-2- (ethoxymethyl)-5-{[4-(2-fluoro-3- methylpyridin- 4-yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 8.05 (br d, J = 4.9 Hz,1H), 7.24-7.37 (m, 2H), 7.13-7.24 (m, 3H), 6.98-7.11 (m, 1H), 6.89 (brd, J = 7.3 Hz, 2H), 5.44 (br s, 1H), 4.25-4.39 (m, 2H), 3.95-4.09 (m,2H), 3.41-3.52 (m, 2H), 3.32 (s, 2H), 2.54- 2.56 (m, 3H), 2.15 (s, 3H),1.02 (br t, J = 1.82, A, 540.2 A 6.6 Hz, 3H) 127

2-butyl-1- [(1S)-1-(3,5- difluorophenyl) propyl]-6- hydroxy-5-{[3-(3-methylpyridin-4- yl)phenyl] methyl}-1,4- dihydropyrimidin- 4-one 1H NMR(DMSO-d6) Shift: 8.46 (br s, 1H), 8.38-8.43 (m, 1H), 6.94-7.48 (m, 6H),6.84-6.91 (m, 2H), 5.15-5.55 (m, 1H), 3.53 (br s, 2H), 2.48- 2.50 (m,3H) 2.31- 2.46 (m, 2H), 2.11- 2.22 (m, 2H), 1.53- 1.68 (m, 2H), 1.27-1.42 (m, 2H), 0.72- 0.90 (m, 6H) 1.97, A, 503.9 B 128

2-butyl-1- [(1S)-1-(3,5- difluorophenyl) propyl]- 5-{[3-(2-fluoro-3-methylpyridin-4- yl)phenyl] methyl}-6- hydroxy-1,4- dihydropyrimidin-4-one 1H NMR (DMSO-d6) Shift: 8.06 (br d, J = 4.5 Hz, 1H), 6.97-7.47 (m,6H), 6.87 (br s, 2H), 5.34 (br s, 1H), 3.49- 3.58 (m, 2H), 2.72- 2.86(m, 2H), 2.06 (br s, 3H), 1.56-1.73 (m, 2H), 1.35 (br s, 2H), 1.17- 1.29(m, 2H), 0.72-0.91 (m, 6H) 2.21, A, 522.2 B 129

2-butyl-1- [(1S)-1-(3,5- difluorophenyl) propyl]- 6-hydroxy-5- {[3-(2-methylpyridin-3- yl)phenyl] methyl}-1,4- dihydropyrimidin- 4-one 1H NMR(DMSO-d6) Shift: 8.36-8.40 (m, 1H), 7.43-7.54 (m, 1H), 6.89-7.40 (m,6H), 6.80 (br d, J = 7.0 Hz, 2H), 5.15-5.44 (m, 1H), 3.45-3.79 (m, 2H),2.44 (br s, 2H), 2.30 (br s, 3H), 1.44-1.62 (m, 2H), 1.25-1.43 (m, 2H),1.16-1.25 (m, 2H), 0.71-0.83 (m, 6H) 2.00, A, 504.0 B 130

2-butyl-1- [(1S)-1-(3,5- difluorophenyl) propyl]- 5-{[3-(6-fluoro-2-methylpyridin-3- yl)phenyl]methyl}- 6-hydroxy-1,4- dihydropyrimidin-4-one 1H NMR (DMSO-d6) Shift: 7.62-7.72 (m, 1H), 6.94-7.43 (m, 7H), 6.85(br d, J = 7.0 Hz, 2H), 5.34 (br s, 1H), 3.61- 3.69 (m, 2H), 2.31- 2.44(m, 2H), 2.25 (br s, 3H), 1.44-1.66 (m, 2H), 1.27-1.41 (m, 2H),1.15-1.27 (m, 2H), 0.64-0.97 (m, 6H) 2.20, A, 522.3 A 131

3′-({2-butyl-1- [(1S)-1-(3,5- difluorophenyl) propyl]-6-hydroxy-4-oxo-1,4- dihydropyrimidin-5- yl}methyl)-4-fluoro- [1,1′-biphenyl]-2-carboxamide 1H NMR (DMSO-d6) Shift: 7.70 (br s, 1H), 6.98-7.40 (m, 8H),6.85- 6.92 (m, 1H), 5.15-5.49 (m, 1H), 3.61 (br s, 2H), 2.63-2.93 (m,2H), 2.29- 2.47 (m, 2H), 1.46-1.67 (m, 2H), 1.26-1.42 (m, 2H), 0.69-0.95(m, 6H) 1.89, A, 550.2 B 132

1- [(1S)-1-(3,5- difluorophenyl) propyl]-2-(1- ethyl-1H-pyrazol-3-methylpyridin-4- yl)phenyl]methyl}- 6-hydroxy-1,4- dihydropyrimidin-4-one 1H NMR (DMSO-d6) Shift: 8.05 (br d, J = 4.9 Hz, 1H), 7.88 (br s,1H), 7.26 (s, 4H), 7.18 (br d, J = 4.9 Hz, 1H), 7.01- 7.11 (m, 1H),6.92-7.01 (m, 2H), 6.70 (br s, 1H), 5.98-6.18 (m, 1H), 4.16 (q, J = 7.0Hz, 2H), 3.53-3.67 (m, 2H), 2.19- 2.35 (m, 2H), 2.13 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H), 0.75 (br t, J = 7.2 2.11, A, 560.3 A Hz, 3H) 133

1-[(1S)-1-(3,5- difluorophenyl) propyl]-2-(1-ethyl- 1H-pyrazol-3-yl)-6-hydroxy- 5-{[4-(2- methylpyridin-3- yl)phenyl] methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 8.40 (br d, J = 3.2 Hz,1H), 7.87 (br s, 1H), 7.55 (br d, J = 7.4 Hz, 2H), 7.24-7.41 (m, 2H),7.19-7.24 (m, 4H), 7.04 (br t, J = 8.3 Hz, 1H), 6.70 (br s, 1H), 5.98-6.16 (m, 1H), 4.12-4.28 (m, 2H), 3.50-3.69 (m, 2H), 2.38 (s, 3H), 2.27(dt, J = 13.8, 6.8 Hz, 2H), 1.33 (br t, J = 7.2 2.09, A, 542.4 A Hz,3H), 0.75 (br t, J = 7.2 Hz, 3H) 134

1-[(1S)-1-(3,5- difluorophenyl) propyl]-2-(1- ethyl-1H-pyrazol-3-yl)-5-{[4-(6- fluoro-2- methylpyridin-3- yl)phenyl]methyl}-6-hydroxy-1,4- dihydropyrimidin- 4-one 1H NMR DMSO d6 Shift: 7.89 (br s,1H), 7.74 (br t, J = 8.0 Hz, 1H), 7.17-7.30 (m, 4H), 6.92-7.12 (m, 4H),6.69 (br s, 1H), 5.95-6.15 (m, 1H), 4.08-4.28 (m, 2H), 3.77-3.96 (m,2H), 2.31-2.47 (m, 3H), 1.76- 1.97 (m, 2H), 1.26- 1.42 (m, 3H),0.70-0.83 (m, 3H) 2.08, A, 560.3 A 135

1-[(1S)-1-(3,5- difluorophenyl) propyl]-2-(1- ethyl-1H-pyrazol-3-yl)-5-{[4-(6- fluoropyridin-3- yl)phenyl] methyl}-6- hydroxy-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 8.45 (s, 1H), 8.12- 8.27(m, 1H), 7.87 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.19-7.31 (m, 3H), 7.04(br t, J = 8.4 Hz, 1H), 6.97 (br d, J = 7.3 Hz, 2H), 6.69 (br s, 1H),5.98-6.08 (m, 1H), 4.16 (q, J = 7.0 Hz, 2H), 3.70 (br s, 2H), 2.26 (dt,J = 13.7, 6.8 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.75 1.93, A, 546.4 A(t, J = 7.3 Hz, 3H) 136

1-[(1S)-1-(3,5- difluorophenyl) propyl]-2-(1- ethyl-1H-pyrazol-3-yl)-6-hydroxy- 5-{[4-(3- methylpyridin-4- yl)phenyl] methyl}-1,4-dihydropyrimidin- 4-one 1H NMR (DMSO-d6) Shift: 8.32-8.55 (m, 2H), 7.85(br s, 1H), 7.11- 7.39 (m, 5H), 7.00-7.12 (m, 1H), 6.82-7.00 (m, 2H),6.61 (br s, 1H), 5.91 (br s, 1H), 4.07- 4.28 (m, 2H), 3.57 (br s, 2H),2.49 (s, 3H), 2.16-2.30 (m, 2H), 1.27- 1.42 (m, 3H), 0.69- 0.89 (m, 3H)1.89, A, 540.1 A

1. A compound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: alk is C₁₋₆ alkylsubstituted with 1-5 R⁴; ring A is independently selected from 5- or6-membered aryl and heteroaryl comprising carbon atoms and 1-4heteroatoms selected from N, NR^(3a), O, and S, each substituted with1-3 R³ ring B is independently selected from aryl, heteroaryl, andcycloalkyl, each substituted with 1-4 R¹; R¹ is independently selectedfrom H, halogen, NO₂, —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R^(c), C₁₋₄ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R² is independentlyselected from C₂₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenylsubstituted with 0-3 R^(e), aryl substituted with 1-3 R^(e),heterocyclyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl substitutedwith 0-3 R^(e); provided when R² is C₂₋₅ alkyl, the carbon atom and thegroups attached thereto except the one attached to the pyrimidine ringmay be replaced by O, N, and S; R³ is independently selected from H,halogen, —(CH₂)_(n)OR^(b), —(CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R^(c), C₁₋₅ alkyl substituted with 0-3 R^(e),(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(3a), O, S, and substituted with 0-3 R^(e); R^(3a)is independently selected from H, —S(O)_(p)R_(c), —C(═O)R^(b),—C(═O)NR^(a)R^(a), —C(═O)OR^(b), —S(O)_(p)NR^(a)R^(a), C₁₋₅ alkylsubstituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R⁴ isindependently selected from C₁₋₅ alkyl substituted with 0-3 R^(e),(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); orR^(a) and R^(a) together with the nitrogen atom to which they are bothattached form a heterocyclic ring substituted with 0-5 R^(e); R^(b), ateach occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); R^(c), at each occurrence, is independently selected fromC₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5R^(e), C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, andheterocyclyl; R^(d), at each occurrence, is independently selected fromH and C₁₋₆ alkyl substituted with 0-5 R^(e); R^(e), at each occurrence,is independently selected from C₁₋₆ alkyl (optionally substituted withhalogen, OH, and CN), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H, —(CH₂)_(n)OR_(f),S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f),NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and—(CH₂)_(n)NR^(f)R^(f); R^(f), at each occurrence, is independentlyselected from H, C₁₋₅alkyl (optionally substituted with halogen and OH),C₃₋₆ cycloalkyl, and phenyl, or R^(f) and R^(f) together with thenitrogen atom to which they are both attached form a heterocyclic ringoptionally substituted with C₁₋₄alkyl; n is independently selected fromzero, 1, 2, and 3; and p, at each occurrence, is independently selectedfrom zero, 1, and
 2. 2. The compound according to claim 1, or astereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein ring A isindependently selected from

ring B is independently selected from

and 6-membered heteroaryl, each substituted with 1-4 R¹; R¹ isindependently selected from H, F, Cl, Br, NO₂, —(CH₂)_(n)OR^(b),(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkylsubstituted with 0-3 R^(e) and C₃₋₆ cycloalkyl substituted with 0-3R^(e); R² is independently selected from C₂₋₅ alkyl substituted with 0-3R^(e); C₂₋₅ alkenyl, aryl substituted with 1-3 R^(e), heterocyclylsubstituted with 0-3 R^(e), and C₃₋₆ cycloalkyl; provided when R² isC₁₋₅ alkyl, the carbon atom and the groups attached thereto except theone attached to the pyrimidine ring may be replaced by O, N, and S; R³is independently selected from H, halogen, —(CH₂)_(n)OR^(b),(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)R^(b),—(CH₂)_(n)NHC(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NHS(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NHS(O)_(p)R_(c), C₁₋₅ alkyl substituted with 0-3 R^(e),(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(3a), O, S, and substituted with 0-3 R^(e); R^(3a)is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)-arylsubstituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-3 R^(e); R^(a), at each occurrence, is independently selected from H,C₁₋₆ alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e); R^(b), at each occurrence, is independently selected from H, C₁₋₆alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from C₁₋₆ alkyl (optionallysubstituted with halogen, OH, and CN), C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,—(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f); R^(f), at each occurrence,is independently selected from H, C₁₋₅alkyl (optionally substituted withhalogen and OH), C₃₋₆ cycloalkyl, and phenyl; n is independentlyselected from zero, 1, 2, and 3; and p, at each occurrence, isindependently selected from zero, 1, and
 2. 3. The compound according toclaim 2 having Formula (II):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: ring A isindependently selected from

R¹ is independently selected from F, Cl, OH, C₁₋₃ alkyl, and OC₁₋₃alkyl; R^(1a) is independently selected from F, Cl, and C₁₋₂ alkyl; R²is independently selected from C₂₋₅ alkyl substituted with 0-3 R^(e);C₂₋₅ alkenyl, aryl substituted with 1-3 R^(e), heteroaryl substitutedwith 0-3 R^(e), C₃₋₆ cycloalkyl and —(CH₂)₁₋₄OC₁₋₅alkyl, and—(CH₂)₁₋₃OC₃₋₆cycloalkyl; R³ is independently selected from H, F, Cl,Br, —OR^(b), —(CH₂)_(n)C(═O)R^(b), (CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)R^(b), C₁₋₄ alkylsubstituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with0-3 R^(e), and —(CH₂)_(n)-heterocyclyl comprising carbon atoms and 1-4heteroatoms selected from N, NR^(3a)O, S, and substituted with 0-3R^(e); R^(3a) is independently selected from H, CH₃, —(CH₂)_(n)-arylsubstituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-3 R^(e); R^(a), at each occurrence, is independently selected from H,C₁₋₆ alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e); R^(b), at each occurrence, is independently selected from H, C₁₋₆alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from C₁₋₆ alkyl (optionallysubstituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, ═O, and CO₂H; and n is independently selected fromzero, 1, 2, and
 3. 4. The compound according to claim 3 having Formula(III):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹ is independentlyselected from C₁₋₃ alkyl and —OC₁₋₃ alkyl; R² is independently selectedfrom C₂₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl, arylsubstituted with 1-3 R^(e), heteroaryl substituted with 0-3 R^(e), C₃₋₆cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl; R³ isindependently selected from H, F, Cl, Br, —OC₁₋₄alkyl, S(O)₂C₁₋₄alkylR^(e), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)NR^(a)R^(a), —C(═O)NR^(a)R^(a), —NHC(═O)R^(b), C₁₋₄ alkylsubstituted with 0-3 R^(e), C₃₋₆ carbocyclyl selected from

and heterocyclyl selected from

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); orR^(a) and R^(a) together with the nitrogen atom to which they are bothattached form a heterocyclic ring substituted with 0-5 R^(e)R^(e), ateach occurrence, is independently selected from C₁₋₆ alkyl (optionallysubstituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and n is independently selectedfrom zero, 1, 2, and
 3. 5. The compound according to claim 4 havingFormula (IIIa):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹ is independentlyselected from C₁₋₃ alkyl and —OC₁₋₃ alkyl; R² is independently selectedfrom C₂₋₅ alkyl substituted with 0-3 R^(e), phenyl substituted with 1-3R^(e), 5-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl; R^(3b) isindependently selected from H, F, Cl, and Br; R^(3c) is independentlyselected from H, (CH₂)_(n)NR^(a)R^(a),

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); orR^(a) and R^(a) together with the nitrogen atom to which they are bothattached form a heterocyclic ring substituted with 0-5 R^(e); R^(e), ateach occurrence, is independently selected from C₁₋₆ alkyl (optionallysubstituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, ═O, CO₂H and CONH₂; and n is independently selectedfrom zero, 1, 2, and
 3. 6. The compound according to claim 5 or astereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R² is independentlyselected from C₂₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl,phenyl substituted with 1-3 R^(e), 5-membered heteroaryl substitutedwith 0-3 R^(e), C₃₋₆ cycloalkyl and CH₂O(CH₂)₁₋₃CH₃; R³ is independentlyselected from H and —(CH₂)₀₋₁NR^(a)R^(a); R^(a) and R^(a) together withthe nitrogen atom to which they are both attached form a heterocyclicring selected from

R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl(optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂.
 7. Acompound according to claim 3, or a stereoisomer, an enantiomer, adiastereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from F, Cl, OH, and OC₁₋₄ alkyl; R^(1a) isindependently selected from F, Cl, and C₁₋₂ alkyl; R² is independentlyselected from C₂₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl,phenyl substituted with 1-3 R^(e), 5- or 6-membered heteroarylsubstituted with 0-3 R^(e), C₃₋₆ cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃; R³ isindependently selected from H, C₁₋₄ alkyl substituted with 0-3 R^(e),and phenyl substituted with 0-3 R^(e); R^(3a) is independently selectedfrom H, CH₃, and —(CH₂)_(n)-phenyl substituted with 0-3 R^(e); andR^(e), at each occurrence, is independently selected from C₁₋₆ alkyl(optionally substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, and CO₂H.
 8. The compoundaccording to claim 1 having Formula (IV):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: ring A isindependently selected from

ring B is independently selected from

R¹ is independently selected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, andC₁₋₄ alkyl; R² is independently selected from C₂₋₅ alkyl substitutedwith 0-3 R^(e); C₂₋₅ alkenyl, phenyl substituted with 1-3 R^(e), 5- or6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl andCH₂O(CH₂)₁₋₃CH₃; R³ is independently selected from H, F, Cl, Br,—OR^(b), —(CH₂)_(n)C(═O)R^(b), (CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NHC(═O)R^(b), C₁₋₄ alkylsubstituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);R^(3a) is independently selected from H, CH₃, —(CH₂)_(n)-arylsubstituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-3 R^(e); R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, and CH₂OCH₃; R^(a), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and R^(a)together with the nitrogen atom to which they are both attached form aheterocyclic ring substituted with 0-5 R^(e); R^(b), at each occurrence,is independently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from C₁₋₆ alkyl (optionallysubstituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and n is independently selectedfrom zero, 1, 2, and
 3. 9. The compound according to claim 8 havingFormula (V):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹ is independentlyselected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, and C₁₋₄ alkyl; R² isindependently selected from —CH₂(CH₂)₁₋₃CH₃, —CH₂OCH(CH₃)₂,—(CH₂)₁₋₃C₃₋₆cycloalkyl,

5-membered heteroaryl selected from

and CH₂O(CH₂)₁₋₃CH₃; R³ is independently selected from H, F, Cl, Br,C₃₋₆ cycloalkyl, phenyl substituted with 0-3 R^(e), and 5- or 6-memberedheteroaryl substituted with 0-3 R^(e); R⁴ is independently selected fromCH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH₂OCH₃; R^(e), at eachoccurrence, is independently selected from C₁₋₆ alkyl (optionallysubstituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, ═O, CO₂H, and CONH₂; and n is independently selectedfrom zero, 1, 2, and
 3. 10. The compound according to claim 9 havingFormula (VI):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹ is independentlyselected from H, F, Cl, Br, OC₁₋₄ alkyl, CN, and C₁₋₄ alkyl; R^(3b) isindependently selected from H and F; R^(3c) is independently selectedfrom

R⁴ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, andCH₂OCH₃; R^(e), at each occurrence, is independently selected from C₁₋₆alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,and CONH₂; and n is independently selected from zero, 1, 2, and
 3. 11. Acompound according claim 1, wherein the compound is selected from theexemplified examples or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and acompound of claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 13. A method of treatingcardiovascular diseases, comprising administering to a patient in needthere of a therapeutically effective amount of the pharmaceuticalcomposition of claim
 12. 14. The method of claim 13 wherein saidcardiovascular diseases are coronary heart disease, stroke, heartfailure, systolic heart failure, diastolic heart failure, diabetic heartfailure, heart failure with preserved ejection fraction, cardiomyopathy,myocardial infarction, left ventricular dysfunction, left ventriculardysfunction after myocardial infarction, cardiac hypertrophy, myocardialremodeling, myocardial remodeling after infarction or after cardiacsurgery and valvular heart diseases.